Aminoethanol derivatives

ABSTRACT

The present invention provides a pharmaceutical agent having cholesteryl ester transfer protein inhibitory action and useful as a blood lipid lowering agent and the like. The present invention relates to a compound represented by the formula 
                 
 
wherein Ar 1  is an aromatic ring group optionally having substituents, Ar 2  is an aromatic ring group having substituents, OR″ is an optionally protected hydroxyl group, R is an acyl group, R′ is a hydrogen atom or a hydrocarbon group optionally having substituents, or a salt thereof, and a pharmaceutical composition containing a compound of the formula (I) or a salt thereof or a prodrug thereof.

TECHNICAL FIELD

The present invention relates to novel aminoethanol derivatives thatinhibit cholesteryl ester transfer protein, and the like.

BACKGROUND ART

A number of epidemiological searches have clarified thathypercholesterolemia, particularly, high level of low densitylipoprotein (LDL)-cholesterol in serum, is a risk factor ofarteriosclerotic diseases (e.g., cardiac infarction, angina pectoris,cerebral infarction and the like). As a pharmaceutical agent to lowerserum LDL-cholesterol, pharmaceutical agents that inhibit3-hydroxy-3-methylglytaryl coenzyme A (HMG-CoA) reductase have beenclinically used, and large scale clinical tests have clarified that theyshow a certain effect on the decrease of incidence of coronary diseases(N. Engl. J. Med., 34, 498-511 (1999)). However, the effect is not fullysatisfactory. In addition, it is epidemiologically known that theconcentration of high density lipoprotein (HDL)—cholesterol in serumshows an inverse correlation with the incidence of coronary diseases (N.Engl. J. Med., 321, 1311-1316 (1989), Am. Heart J., 110, 1100-1107(1985)), and a pharmaceutical agent that increases serum HDL-cholesterolhas been drawing attention as a pharmaceutical agent for the prophylaxisor treatment of arteriosclerotic diseases.

The cholesteryl ester transfer protein (CETP) catalyzes transfer ofcholesteryl ester from HDL to LDL and very low density lipoprotein(VLDL) (J. Lipid Res., 34, 1255-1274 (1993)), and is deeply involved inthe inverse transfer system of cholesterol or transfer of cholesterolfrom peripheral tissues to the liver. As the inverse transfer system ofcholesterol, the following three pathways are known.

-   (1) Free cholesterol accumulated in the peripheral tissues is    extracted by HDL, undergoes the action of lecithin-cholesterol    acyltransferase (LCAT) and converted to cholesteryl ester on HDL.    The cholesteryl ester on HDL is transferred by CETP to LDL or VLDL    in exchange of triglyceride, and cholesterol is transferred to the    liver via LDL receptor.-   (2) HDL becomes apoprotein E-containing HDL and is uptaken into the    liver via LDL receptor.-   (3) Cholesteryl ester on HDL is directly uptaken into the liver via    HDL receptor.

Because CETP is deeply involved in the cholesterol inverse transfersystem, the intensity of its activity in blood is considered to belinked to the control of blood HDL-cholesterol concentration. Withregard to the correlation between CETP and blood HDL—cholesterolconcentration, for example, the following findings are known. When CETPactivity is inhibited by CETP monoclonal antibody in rabbit and hamster,serum HDL—cholesterol concentration increases (J. Clin. Invest., 84,129-137 (1989), Atherosclerosis, 110, 101-109 (1994)). Transgenic mouseand transgenic rat that expressed CETP shows increased LDL-cholesterolconcentration (J. Biol. Chem., 266, 10796-10801 (1991), Nat. Med., 5,1383-1389 (1999)). From epidemiological search, individuals showingdecreased or no CETP activity due to genetic mutation also showincreased blood HDL—cholesterol concentration (Nature, 342, 448-451(1989), Atherosclerosis, 58, 175-186 (1985)).

From the above findings, it is considered that intensity of CETPactivity has an inverse correlation with arteriosclerosis-suppressiveHDL-cholesterol, and inhibition of CETP activity is expected to lowerthe risk of progression of coronary diseases. In fact, it is known thatCETP activity varies depending on the animal species, andarteriosclerosis is induced by cholesterol loading in animals havinghigh CETP activity (rabbit etc.), but arteriosclerosis is not easilyinduced in animals free of CETP (rat and the like). When CETP activitywas inhibited sustainably in rabbit by administration of antisense RNA,blood HDL-cholesterol concentration increased and the progression ofarteriosclerotic lesion was suppressed (J. Biol. Chem., 273, 5033-5036(1998)). Therefore, a pharmaceutical agent that suppresses CETP activityis expected to act suppressively on arteriosclerotic diseases byinhibiting transfer of cholesterol from HDL to LDL or VLDL, increasingarteriosclerosis-suppressive HDL-cholesterol and simultaneouslydecreasing arteriosclerosis-promotive VLDL-cholesterol orLDL-cholesterol. That is, a pharmaceutical agent that suppresses CETPactivity is expected to give a pharmaceutical agent for the prophylaxisor treatment of the diseases such as acute coronary syndrome, acutecardiac infarction, unstable angina pectoris, PTCA or arterialrestenosis after stent placement, peripheral arterial occlusion,hyperlipidemia, cerebral infarction, stroke and the like, or an agentfor suppressing progression of focal arteriosclerosis.

The pharmaceutical agents having CETP inhibitory action are disclosedin, for example, WO99/41237, lipids, 29, 811-818 (1994), WO98/35937,Atherosclerosis, 128, 59-66 (1997), Bioorg. Med. Chem. Lett., 6, 919-922(1996), U.S. Pat. No. 5,925,645, U.S. Pat. No. 5,932,587, Europe patentNo. 825185, Europe patent No. 818448, Angew. Chem., Int. Ed., 38,3373-3375 (1999), WO99/14174, WO00/18724, WO00/17164 and the like.

As the aminoethanol derivatives, for example, JP-A-11-286478 disclosestert-butylbenzyl-[2(S)-hydroxy-2-thiazol-2-yl-1(S)-(4-trifluoromethyl-benzyl)-ethyl]-carbamateas a compound to be a starting material for an antivirus agent,WO99/45928 discloses a compound to be a starting material for a compoundhaving an action of improving autoimmune diseases, JP-A-11-246437discloses a compound to be a starting material for a compound having agastrointestinal mucosal protective action, WO98/18794 discloses acompound to be a starting material for a compound having a chymaseinhibitory action, Lett. Pept. Sci., 2, 229-232 (1995) discloses acompound to be a starting material for a compound having an HIV-1protease inhibitory action and a DPP-IV inhibitory action, WO93/25574discloses a compound to be a starting material for a compound having aangiotensin I chymase inhibitory action, WO89/10752 discloses a compoundto be a starting material for a compound having a retroviral proteaseinhibitory action, EP No. 231919 discloses a compound having a renininhibitory action, and French Patent No. 1578851 discloses a compoundhaving an adrenergic action, but no disclosure is found that thesecompounds have a prophylactic or therapeutic action on arterioscleroticdiseases or any description suggestive thereof.

As a pharmaceutical agent that increases plasma HDL-cholesterol (HDL-C),fibrate-type pharmaceutical agents and nicotinic acid have been used.They show an indirect HDL-C increasing action and side effects are aconcern. As the situation stands, the development of a novelpharmaceutical agent that directly increases HDL-cholesterol and affordsa sufficiently satisfactory effect in the prophylaxis or treatment ofarteriosclerotic diseases such as ischemic heart and brain diseases,peripheral arterial occlusion and the like is awaited.

DISCLOSURE OF THE INVENTION

The present inventors have found that aminoethanol derivatives havingthe following specific substituents increase plasma HDL-C by inhibitingcholesterol ester transfer protein (CETP) and have a superiorprophylactic or therapeutic effect on arteriosclerotic diseases, whichresulted in the completion of the present study.

Accordingly, the present invention relates to:

-   (1) a compound represented by the formula

wherein

-   Ar¹ is an aromatic ring group optionally having substituents,-   Ar² is an aromatic ring group having substituents,-   OR″ is an optionally protected hydroxyl group,-   R is an acyl group, and-   R′ is a hydrogen atom or a hydrocarbon group optionally having    substituents,-   or a salt thereof,-   except tert-butyl    benzyl-[2(S)-hydroxy-2-thiazol-2-yl-1(S)-(4-trifluoromethyl-benzyl)-ethyl]-carbamate;-   (2) the compound of the aforementioned (1), wherein Ar¹ is a 5- or    6-membered aromatic ring group optionally having substituents;-   (3) the compound of the aforementioned (1), wherein Ar¹ is a phenyl    group optionally having substituents;-   (4) the compound of the aforementioned (1), wherein Ar² is a 5- or    6-membered aromatic ring group having substituents;-   (5) the compound of the aforementioned (1), wherein Ar² is a phenyl    group having substituents;-   (6) the compound of the aforementioned (1), wherein R is a group    represented by the formula R^(1N)CO— (R^(1N) is a hydrocarbon group    optionally having substituents or a heterocyclic group optionally    having substituents);-   (7) the compound of the aforementioned (6), wherein R^(1N) is a    cyclic hydrocarbon group optionally having substituents or a    heterocyclic group optionally having substituents;-   (8) the compound of the aforementioned (1), wherein R″ is a hydrogen    atom or an acyl group;-   (9) the compound of the aforementioned (1), wherein R″ is a group    represented by the formula R^(1O)CO— (R^(1O) is a hydrocarbon group    optionally having substituents or a heterocyclic group optionally    having substituents);-   (10) the compound of the aforementioned (8), wherein R^(1O) is an    alkyl group optionally having substituents;-   (11) the compound of the aforementioned (1), wherein R″ is a    hydrogen atom;-   (12) the compound of the aforementioned (1), wherein R′ is a    hydrogen atom;-   (13) the compound of the aforementioned (1), wherein R is a group    represented by the formula R^(1N)CO— (R^(1N) is a cyclic hydrocarbon    group optionally having substituents or a heterocyclic group    optionally having substituents), R″ is a hydrogen atom and R′ is a    hydrogen atom;-   (14) the compound of the aforementioned (1), wherein Ar¹ is a 5- or    6-membered aromatic ring group optionally having substituents    selected from halogen atom, optionally halogenated lower alkyl    group, optionally halogenated lower alkoxy group and aryloxy group    optionally having substituents, Ar² is a 5- or 6-membered aromatic    ring group having substituents selected from halogen atom,    optionally halogenated lower alkyl group and optionally halogenated    lower alkoxy group, R is a C₁₋₆ alkoxy-carbonyl, a C₁₋₆    alkyl-carbonyl, a C₆₋₁₀ aryl-carbonyl, dihydronaphthalenecarbonyl,    tetrahydronaphthalenecarbonyl, benzocycloheptenecarbonyl or    benzocyclooctenecarbonyl, each of which may have substituent(s)    selected from halogen atom, optionally halogenated C₁₋₆ alkoxy and    optionally halogenated C₁₋₆ alkyl, R″ is a hydrogen atom, and R′ is    a hydrogen atom;-   (15) the compound of the aforementioned (14), wherein the 5- or    6-membered aromatic ring group is a phenyl group, a pyridyl group, a    thienyl group, a furyl group or a thiazolyl group;-   (16) the compound of the aforementioned (14), wherein the 5- or    6-membered aromatic ring group is a phenyl group, a pyridyl group or    a thienyl group, and R is naphthalenecarbonyl,    dihydronaphthalenecarbonyl, tetrahydronaphthalenecarbonyl,    benzocycloheptenecarbonyl or benzocyclooctenecarbonyl, each of which    may have substituent(s) selected from halogen atom, optionally    halogenated C₁₋₆ alkoxy and optionally halogenated C₁₋₆ alkyl;-   (17) the compound of the aforementioned (1), which is    N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,    4-fluoro-N-((1R,2S)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide,    N-[(1R,2S)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,    N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-5,6-dihydronaphthalene-1-carboxamide,    N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-1-carboxamide,    4-fluoro-N-[(1R,2S)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]naphthalene-1-carboxamide,    N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-5,6,7,8-tetrahydrobenzo[a]cyclooctene-1-carboxamide,    N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-(4-isopropylbenzyl)ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,    N-((1RS,2SR)-2-(3-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,    N-((1RS,2SR)-2-hydroxy-2-(4-phenoxyphenyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,    N-[(1RS,2SR)-2-(4-chlorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,    N-((1RS,2SR)-2-hydroxy-2-(4-(phenyloxy)phenyl)-1-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,    N-((1RS,2SR)-2-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-2-hydroxy-1-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,    N-((1RS,2SR)-2-(2-fluoropyridin-4-yl)-2-hydroxy-1-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,    N-((1RS,2RS)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,    N-[(1RS,2SR)-1-(4-tert-butylbenzyl)-2-(3-chlorophenyl)-2-hydroxyethyl]-5-chloro-1-naphthamide,    4-fluoro-N-{(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]ethyl}-1-naphthamide    or a salt thereof;-   (18) a prodrug of a compound represented by the formula-   wherein-   Ar¹ is an aromatic ring group optionally having substituents,-   Ar² is an aromatic ring group having substituents,-   OR″ is an optionally protected hydroxyl group,-   R is an acyl group, and-   R′ is a hydrogen atom or a hydrocarbon group optionally having    substituents,-   or a salt thereof,-   except tert-butyl    benzyl-[2(S)-hydroxy-2-thiazol-2-yl-1(S)-(4-trifluoromethyl-benzyl)-ethyl]-carbamate;-   (19) a pharmaceutical composition comprising a compound represented    by the formula-   wherein-   Ar¹ is an aromatic ring group optionally having substituents,-   Ar² is an aromatic ring group having substituents,-   OR″ is an optionally protected hydroxyl group,-   R is an acyl group, and-   R′ is a hydrogen atom or a hydrocarbon group optionally having    substituents,-   or a salt thereof or a prodrug thereof;-   (20) the composition of the aforementioned (19), which is a    cholesteryl ester transfer protein inhibitor;-   (21) the composition of the aforementioned (19), which is a high    density lipoprotein—cholesterol elevating agent;-   (22) the composition of the aforementioned (19), which is a low    density lipoprotein—cholesterol lowering agent;-   (23) the composition of the aforementioned (19), which is an very    low density lipoprotein—cholesterol lowering agent;-   (24) the composition of the aforementioned (19), which is a    triglyceride lowering agent;-   (25) the composition of the aforementioned (19), which is a    prophylactic or therapeutic agent of acute coronary syndrome;-   (26) the composition of the aforementioned (19), which is a    prophylactic or therapeutic agent of acute cardiac infarction;-   (27) the composition of the aforementioned (19), which is a    prophylactic or therapeutic agent of unstable angina pectoris;-   (28) the composition of the aforementioned (19), which is a    prophylactic or therapeutic agent of PTCA or arterial restenosis    after stent placement;-   (29) the composition of the aforementioned (19), which is a    prophylactic or therapeutic agent of peripheral arterial occlusion;-   (30) the composition of the aforementioned (19), which is a    prophylactic or therapeutic agent of hyperlipidemia;-   (31) the composition of the aforementioned (19), which is a    prophylactic or therapeutic agent of cerebral infarction;-   (32) the composition of the aforementioned (19), which is a    prophylactic or therapeutic agent of stroke;-   (33) the composition of the aforementioned (19), which is a    suppressor of progression of focal arteriosclerosis;-   (34) a cholesteryl ester transfer protein inhibitor comprising a    compound represented by the formula-   wherein-   Ar¹ is an aromatic ring group optionally having substituents,-   Ar² is an aromatic ring group optionally having substituents,-   OR″ is an optionally protected hydroxyl group,-   R is an acyl group, and-   R′ is a hydrogen atom or a hydrocarbon group optionally having    substituents,-   or a salt thereof or a prodrug thereof;-   (35) the agent of the aforementioned (34), which is a prophylactic    or therapeutic agent of hyperlipidemia;-   (36) the agent of the aforementioned (34), which is a prophylactic    or therapeutic agent of acute coronary syndrome;-   (37) the agent of the aforementioned (34), which is a prophylactic    or therapeutic agent of acute cardiac infarction;-   (38) the agent of the aforementioned (34), which is a prophylactic    or therapeutic agent of unstable angina pectoris;-   (39) the agent of the aforementioned (34), which is a prophylactic    or therapeutic agent of PTCA or arterial restenosis after stent    placement;-   (40) the agent of the aforementioned (34), which is a prophylactic    or therapeutic agent of peripheral arterial occlusion;-   (41) the agent of the aforementioned (34), which is a prophylactic    or therapeutic agent of cerebral infarction;-   (42) the agent of the aforementioned (34), which is a prophylactic    or therapeutic agent of stroke;-   (43) the agent of the aforementioned (34), which is a suppressor of    progression of focal arteriosclerosis;-   (44) a method of inhibiting cholesteryl ester transfer protein in a    mammal, which comprises administering an effective amount of a    compound of the aforementioned (1) or a salt thereof to the mammal;-   (45) a method for the prophylaxis or treatment of hyperlipidemia in    a mammal, which comprises administering an effective amount of a    compound of the aforementioned (1) or a salt thereof to the mammal;-   (46) use of a compound of the aforementioned (1) or a salt thereof    for the production of a pharmaceutical agent for inhibiting    cholesteryl ester transfer protein;-   (47) use of a compound of the aforementioned (1) or a salt thereof    for the production of a pharmaceutical agent for the prophylaxis or    treatment of hyperlipidemia;-   (48) a method for the prophylaxis or treatment of acute coronary    syndrome in a mammal, which comprises administering an effective    amount of a compound of the aforementioned (1) or a salt thereof to    the mammal;-   (49) a method for the prophylaxis or treatment of acute cardiac    infarction in a mammal, which comprises administering an effective    amount of a compound of the aforementioned (1) or a salt thereof to    the mammal;-   (50) a method for the prophylaxis or treatment of unstable angina    pectoris in a mammal, which comprises administering an effective    amount of a compound of the aforementioned (1) or a salt thereof to    the mammal;-   (51) a method for the prophylaxis or treatment of PTCA or coronary    restenosis after stent placement in a mammal, which comprises    administering an effective amount of a compound of the    aforementioned (1) or a salt thereof to the mammal;-   (52) a method for the prophylaxis or treatment of peripheral    arterial occlusion in a mammal, which comprises administering an    effective amount of a compound of the aforementioned (1) or a salt    thereof to the mammal;-   (53) a method for the prophylaxis or treatment of cerebral    infarction in a mammal, which comprises administering an effective    amount of a compound of the aforementioned (1) or a salt thereof to    the mammal:-   (54) a method for the prophylaxis or treatment of stroke in a    mammal, which comprises administering an effective amount of a    compound of the aforementioned (1) or a salt thereof to the mammal;-   (55) a method of suppressing progression of focal arteriosclerosis    in a mammal, which comprises administering an effective amount of a    compound of the aforementioned (1) or a salt thereof to the mammal;-   (56) use of a compound of the aforementioned (1) or a salt thereof    for the production of a prophylactic or therapeutic agent of acute    coronary syndrome;-   (57) use of a compound of the aforementioned (1) or a salt thereof    for the production of a prophylactic or therapeutic agent of acute    cardiac infarction;-   (58) use of a compound of the aforementioned (1) or a salt thereof    for the production of a prophylactic or therapeutic agent of    unstable angina pectoris;-   (59) use of a compound of the aforementioned (1) or a salt thereof    for the production of a prophylactic or therapeutic agent of    peripheral arterial occlusion;-   (60) use of a compound of the aforementioned (1) or a salt thereof    for the production of a prophylactic or therapeutic agent of    hyperlipidemia;-   (61) use of a compound of the aforementioned (1) or a salt thereof    for the production of a prophylactic or therapeutic agent of    cerebral infarction;-   (62) use of a compound of the aforementioned (1) or a salt thereof    for the production of a prophylactic or therapeutic agent of stroke;-   (63) use of a compound of the aforementioned (1) or a salt thereof    for the production of a suppressor of progression of focal    arteriosclerosis;-   (64) a method of inhibiting cholesteryl ester transfer protein in a    mammal, which comprises administering an effective amount of a    compound represented by the formula (I′) of the aforementioned (34)    or a salt thereof or a prodrug thereof to the mammal;-   (65) use of a compound represented by the formula (I′) of the    aforementioned (34) or a salt thereof or a prodrug thereof for the    production of a pharmaceutical agent for inhibiting cholesteryl    ester transfer protein;-   (66) a production method of the aforementioned (1) or a salt    thereof, which comprises subjecting a compound represented by the    formula-   wherein each symbol is as defined in the aforementioned (1), or a    salt thereof to an acylation reaction to give a compound represented    by the formula-   wherein each symbol is as defined in the aforementioned (1), or a    salt thereof, and, where desired, subjecting the compound to a    hydroxyl group-protecting reaction; and the like.

For the term “acyl group” used in the present specification, acyl groupsobtained by removing OH group from carboxylic acids such as R¹COOH,R¹OCOOH and the like, sulfonic acids such as R¹SO₃H and the like,sulfinic acids such as R¹SO₂H and the like, phosphoric acids such asR¹OPO(OR²)OH and the like, carbamic acids such as R¹N(R²)COOH and thelike (R¹ is a hydrocarbon group optionally having substituents or aheterocyclic group optionally having substituents, and R² is a hydrogenatom or a hydrocarbon group optionally having substituents) and the likeare used. Specifically, R¹CO, R¹OCO, R¹SO₂, R¹SO, R¹OPO(OR²) R¹N(R²)CO(R¹ is a hydrocarbon group optionally having substituents or aheterocyclic group optionally having substituents and R² is a hydrogenatom or a hydrocarbon group optionally having substituents) and the likeare used.

The “hydrocarbon group” of the term “optionally substituted hydrocarbongroup” used in the present specification means, for example, alkylgroup, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynylgroup, aralkyl group, aryl group and the like.

As the substituent that the “hydrocarbon group” optionally has, thosesimilar to the substituent that the “alkyl group” and “cycloalkyl group”to be mentioned below may have, and the like are used.

As the “alkyl group”, for example, “linear or branched C₁₋₁₅ alkylgroups” such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,undecyl, tridecyl, tetradecyl, pentadecyl and the like, and the like areused.

As the “cycloalkyl group”, for example, “C₃₋₁₀ cycloalkyl groups” suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, adamantyl and the like, and the like are used.

As the substituent that the “alkyl group” and “cycloalkyl group” mayhave, for example, (i) nitro group, (ii) hydroxy group, oxo group, (iii)cyano group, (iv) carbamoyl group, (v) mono- or di-C₁₋₄ alkyl-carbamoylgroup (e.g., N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl and the like), mono- or di-phenyl-carbamoyl group,mono- or di-benzyl-carbamoyl group, carboxyl-carbamoyl group, C₁₋₄alkoxy-carbonyl-carbamoyl group, (vi) carboxyl group, (vii) C₁₋₄alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl and the like), (viii) sulfo group(—SO₂OH), (ix) halogen atom (e.g., fluorine, chlorine, bromine, iodineand the like), (x) optionally halogenated C₁₋₄ alkoxy group (e.g.,methoxy, ethoxy, propoxy, isopropoxy and the like), C₁₋₄ alkoxy groupoptionally substituted by hydroxy group, C₁₋₄ alkoxy group optionallysubstituted by carboxyl group, C₁₋₄ alkoxy group optionally substitutedby C₁₋₄ alkoxy-carbonyl group, C₁₋₄ alkoxy-C₁₋₄ alkoxy group, (xi)phenoxy group, phenoxy-C₁₋₄ alkyl group, phenoxy-C₁₋₄ alkoxy group,(xii) optionally halogenated phenyl group, optionally halogenatedphenyl-C₁₋₄ alkyl group, optionally halogenated phenyl-C₂₋₄ alkenylgroup, optionally halogenated phenoxy group (e.g., o-, m- orp-chlorophenoxy, o-, m- or p-bromophenoxy and the like), pyridyloxygroup, C₃₋₁₀ cycloalkyl group, C₃₋₁₀ cycloalkyl-C₁₋₄ alkoxy group, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl group, (xiii) optionally halogenated C₁₋₄ alkylgroup, optionally halogenated C₂₋₄ alkenyl group, optionally halogenatedC₁₋₄ alkylthio group (e.g., methylthio, ethylthio, n-propylthio,isopropylthio, n-butylthio and the like), C₁₋₄ alkyl group optionallysubstituted by hydroxy group, C₁₋₄ alkylthio group optionallysubstituted by hydroxy group, (xiv) mercapto group, thioxo group, (xv)benzyloxy group or benzylthio group optionally substituted bysubstituent(s) selected from halogen atom, carboxyl group and C₁₋₄alkoxy-carbonyl group, (xvi) optionally halogenated phenylthio group,pyridylthio group, phenylthio-C₁₋₄ alkyl group, pyridylthio-C₁₋₄ alkylgroup, (xvii) optionally halogenated C₁₋₄ alkylsulfinyl group (e.g.,methylsulfinyl, ethylsulfinyl and the like), phenylsulfinyl group,phenylsulfinyl-C₁₋₄ alkyl group, (xviii) optionally halogenated C₁₋₄alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl and the like),phenylsulfonyl group, phenylsulfonyl-C₁₋₄ alkyl group, (xix) aminogroup, aminosulfonyl group, (xx) C₁₋₃ acylamino group (e.g.,acetylamino, propionylamino and the like), benzyloxycarbonylamino, (xxi)mono- or di-C₁₋₄ alkylamino group (e.g., methylamino, ethylamino,dimethylamino, diethylamino and the like), (xxii) 4- to 6-memberedcyclic amino group (e.g., 1-azetidinyl, 1-pyrrolidinyl, piperidino,morpholino, thiomorpholino, 1-piperazinyl and the like), 4- to6-membered cyclic amino-carbonyl group (e.g., 1-azetidinylcarbonyl,1-pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl,thiomorpholinocarbonyl, 1-piperazinylcarbonyl and the like), 4- to6-membered cyclic amino-C₁₋₄ alkyl group, (xxiii) C₁₋₆ acyl group (e.g.,formyl, optionally halogenated C₂₋₆ alkanoyl such as acetyl etc., andthe like), (xxiv) benzoyl group optionally substituted by halogen atom,(xxv) 5- to 10-membered heterocyclic group (e.g., 2- or 3-thienyl, 2- or3-furyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or5-isothiazolyl, 2-, 4- or 5-oxazolyl, 1,2,3- or 1,2,4-triazolyl, 1H- or2H-tetrazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 3- or4-pyridazinyl, quinolyl, isoquinolylindolyl and the like), (xxvi) 5- to10-membered heterocyclic-carbonyl group (e.g., 2- or 3-thienylcarbonyl,2- or 3-furylcarbonyl, 3-, 4- or 5-pyrazolylcarbonyl, 2-, 4- or5-thiazolylcarbonyl, 3-, 4- or 5-isothiazolylcarbonyl, 2-, 4- or5-oxazolylcarbonyl, 1,2,3- or 1,2,4-triazolylcarbonyl, 1H- or2H-tetrazolylcarbonyl, 2-, 3- or 4-pyridylcarbonyl, 2-, 4- or5-pyrimidinylcarbonyl, 3- or 4-pyridazinylcarbonyl, quinolylcarbonyl,isoquinolylcarbonyl, indolylcarbonyl and the like), (xxvii) optionallyhalogenated linear or branched C₂₋₅ alkyleneoxy group (e.g.,ethyleneoxy, propyleneoxy, isobutyleneoxy and the like) and (xxviii)optionally halogenated linear or branched C₁₋₄ alkylenedioxy group(e.g., methylenedioxy, ethylenedioxy, propylenedioxy,tetrafluoroethylenedioxy and the like) and the like are used. The “alkylgroup” and “cycloalkyl group” may have 1 to 5 of these substituents atsubstitutable positions.

Preferable “alkyl group” includes, for example, linear or branched C₁₋₆alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl and the like, and as thesubstituent that the “C₁₋₆ alkyl group” may have, for example, 1 to 3 ofhalogen atom, C₁₋₄ alkoxy group, hydroxy group, C₁₋₄ alkoxy-carbonylgroup, carboxyl group, carbamoyl group, mono- or di-C₁₋₄ alkylcarbamoylgroup, pyridylthio group and the like are used.

As the “alkenyl group”, for example, “C₂₋₁₈ alkenyl group” such asvinyl, allyl, isopropenyl, 3-butenyl, 3-octenyl, 9-octadecenyl and thelike, and the like are used.

As the “cycloalkenyl group”, for example, “C₃₋₈ cycloalkenyl group” suchas cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl and the like, and the like are used.

As the substituent that the “alkenyl group” and “cycloalkenyl group” mayhave, those similar to the substituents that the aforementioned “alkylgroup” may have are used.

Preferable “alkenyl group” includes, for example, C₂₋₆ alkenyl groupsuch as vinyl, allyl, 2-butenyl, 3-butenyl and the like, and the like.As the substituent that the “C₂₋₆ alkenyl group” may have, those similarto the substituents that the aforementioned “C₁₋₆ alkyl group” may haveare used.

As the “alkynyl group”, for example, “C₂₋₁₈ alkynyl group” such asethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl and the like, and the like are used.

As the substituent that the “alkynyl group” may have, those similar tothe substituents that the aforementioned “alkyl group” may have areused.

Preferable “alkynyl group” includes, for example, C₂₋₆ alkynyl groupssuch as ethynyl, propynyl, 1-butynyl, 2-butynyl and the like, and thelike. As the substituent that the “C₂₋₆ alkynyl group” may have, thosesimilar to the substituents that the aforementioned “C₁₋₆ alkyl group”may have are used.

As the “aralkyl group”, C₇₋₁₆ aralkyl group and the like are used, andspecifically, phenyl-C₁₋₆ alkyl groups such as benzyl, phenethyl,3-phenylpropyl, 4-phenylbutyl and the like, naphthyl-C₁₋₆ alkyl groupssuch as (1-naphthyl)methyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl andthe like, and the like are used.

As the substituent that the “aralkyl group” may have, the substituentsthat the aforementioned “alkyl group” may have, as well as halogen atom(e.g., fluorine, chlorine, bromine, iodine and the like), C₁₋₄ alkylgroup (e.g., methyl, ethyl, propyl, isopropyl, butyl and the like), C₂₋₆alkenyl group (e.g., vinyl, allyl, 2-butenyl, 3-butenyl and the like),C₁₋₃ acyl group (e.g., formyl, acetyl and the like), C₁₋₄ alkoxy group(e.g., methoxy, ethoxy, propoxy, isopropoxy and the like), nitro group,cyano group, hydroxy group, C₁₋₄ alkoxy-carbonyl group (e.g.,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl andthe like), carbamoyl group, mono- or di-C₁₋₄ alkyl-carbamoyl group(e.g., N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl and the like), mono- or di-C₁₋₄ alkenyl-carbamoylgroup (e.g., N-vinylcarbamoyl and the like) and the like are mentioned,wherein the “aralkyl group” may have 1 to 4 of these substituents atsubstitutable positions.

As the “aryl group”, for example, aromatic monocyclic, bicyclic ortricyclic C₆₋₁₄ aryl group such as phenyl, 1-naphthyl, 2-naphthyl,phenanthryl, anthryl and the like, biphenyl group, tolyl group and thelike are used.

As the substituent that the “aryl group” may have, the substituents thatthe aforementioned “aralkyl group” may have, as well as oxo group andthe like can be used. The “aryl group” may have 1 to 4, preferably 1 or2, of these substituents at substitutable positions. As the aryl grouphaving an oxo group, for example, benzoquinonyl, naphthoquinonyl,anthraquinonyl and the like can be mentioned.

When the “hydrocarbon group” is cycloalkyl group, aryl group or aralkylgroup, for example, it may be substituted by C₁₋₁₀ alkyl group (e.g.,methyl, ethyl, propyl, isopropyl, decyl and the like), C₂₋₁₀ alkenylgroup (e.g., vinyl, allyl, 2-butenyl, 3-butenyl and the like),phenyl-C₂₋₄ alkenyl group (e.g., phenylethenyl and the like), mono- ordi-C₁₋₆ alkenyl-carbamoyl group (e.g., N-vinylcarbamoyl and the like),C₆₋₁₄aryl group (e.g., phenyl, 1-naphthyl, 2-naphthyl), C₇₋₂₀ aralkylgroup (e.g., benzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl,5-phenylpentyl, 6-phenylhexyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyland the like), styryl group, oxo group and the like, wherein the“hydrocarbon group” may have 1 to 4 “substituents” at substitutablepositions.

When the “hydrocarbon group” is a cyclic group such as cycloalkyl group,cycloalkenyl group, aralkyl group, aryl group and the like, it may havea substituent such as optionally halogenated C₁₋₄ alkylenedioxy group,optionally halogenated C₂₋₅ alkyleneoxy group and the like, or thesecyclic groups may be condensed with each other to form a bicyclic ortricyclic fused hydrocarbon group, wherein the fused hydrocarbon groupmay have a group similar to the substituent that the aforementioned“alkyl group” may have.

For the term “heterocyclic group” of the “heterocyclic group optionallyhaving substituents” used in the present specification, a 5- to8-membered ring or a fused ring thereof (including condensation withbenzene ring) having, besides the carbon atom, 1 to 4 hetero atomsselected from oxygen atom, sulfur atom, nitrogen atom and the like, suchas a 5-membered ring group having, besides the carbon atom, 1 to 4hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom andthe like, such as 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-,4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4-or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or5-(1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5-(1,2,4-thiadiazolyl),1,3,4-thiadiazolyl, 4- or 5-(1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H-tetrazolyl and the like; a6-membered ring group having, besides the carbon atom, 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and thelike, such as 2-, 3- or 4-pyridyl, N-oxide-2-, 3- or 4-pyridyl, 2-, 4-or 5-pyrimidinyl, N-oxide-2-, 4- or 5-pyrimidinyl; thiomorpholinyl,morpholinyl, oxoimidazolyl, dioxotriazinyl, pyrrolidinyl, piperidinyl,pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl,piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl,N-oxide-3- or 4-pyridazinyl and the like; a bicyclic or tricyclic fusedring group having, besides the carbon atom, 1 to 4 hetero atoms selectedfrom oxygen atom, sulfur atom, nitrogen atom and the like, such asbenzofuryl, benzothiazolyl, benzooxazolyl, tetrazolo[1,5-b]pyridazinyl,triazolo[4,5-b]pyridazinyl, benzoimidazolyl, quinolyl, isoquinolyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl,quinolizinyl, 1,8-naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl,carbazolyl, acrydinyl, phenanthridinyl, chromanyl, benzoxazinyl,phenazinyl, phenothiazinyl, phenoxazinyl etc., and the like; and thelike are used.

As the “substituent” of the “heterocyclic group optionally havingsubstituents”, groups similar to the “substituent” mentioned for theaforementioned “hydrocarbon group optionally having substituents” andthe like, particularly, the substituent when the “hydrocarbon group” iscycloalkyl group, aryl group or aralkyl group, and the like are used,wherein 1 to 5, preferably 1 or 2, substituents may be present atsubstitutable positions on the heterocyclic ring.

The term “lower alkyl group” used in the present specification shows,for example, a linear or branched alkyl group having 1 to 6 carbonatoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl and the like, and the like.

In the aforementioned formulas, Ar¹ denotes an aromatic ring groupoptionally having substituents and Ar² denotes an aromatic ring grouphaving substituents.

As the “substituent” that the “aromatic ring group” of the “aromaticring group optionally having substituents” for Ar¹ may have and the“substituent” that the “aromatic ring group” of the “aromatic ring grouphaving substituents” for Ar² has, the groups mentioned as the“substituent” of the aforementioned “hydrocarbon group optionally havingsubstituents” and the like are used, wherein 1 to 5, preferably 1 or 2,substituents may be present at substitutable positions of the aromaticring group.

As the “substituent” that the “aromatic ring group” of the “aromaticring group optionally having substituents” for Ar¹ may have, halogenatom, optionally halogenated lower alkyl group, optionally halogenatedlower alkoxy group, aryloxy group optionally having substituents (e.g.,phenoxy group and the like) and the like are preferable. The position ofsubstitution when the “aromatic ring group” of the “aromatic ring groupoptionally having substituents” for Ar¹ is phenyl and the phenyl has onesubstituent is preferably the meta position or para position.

As the “substituent” that the “aromatic ring group” of the “aromaticring group having substituents” for Ar² may have, halogen atom,optionally halogenated lower alkyl group, optionally halogenated loweralkoxy group and the like are preferable. The position of substitutionwhen the “aromatic ring group” of the “aromatic ring group havingsubstituents” for Ar² is phenyl and the phenyl has one substituent ispreferably the meta position or para position.

As the “aromatic ring group” of the “aromatic ring group optionallyhaving substituents” for Ar¹ and the “aromatic ring group” of the“aromatic ring group having substituents” for Ar², aryl group,heteroaryl group and the like are mentioned.

As the “aryl group”, for example, aromatic monocyclic, bicyclic ortricyclic C₆₋₁₄ aryl group such as phenyl, 1-naphthyl, 2-naphthyl,phenanthryl, anthryl and the like, biphenyl group, tolyl group and thelike are used, with preference given to phenyl.

As the “heteroaryl group”, for example, a 5-membered aromatic ring grouphaving, besides the carbon atom, 1 to 4 hetero atoms selected fromoxygen atom, sulfur atom, nitrogen atom and the like, such as 2- or3-thienyl, 2- or 3-furyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl,3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl,3-, 4- or 5-isothiazolyl, 3- or 5-(1,2,4-oxadiazolyl),1,3,4-oxadiazolyl, 3- or 5-(1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4-or 5-(1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1H- or 2H-tetrazolyl and the like; a 6-memberedaromatic ring group having, besides the carbon atom, 1 to 4 hetero atomsselected from oxygen atom, sulfur atom, nitrogen atom and the like, suchas 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, pyridazinyl, pyrazinyland the like; a fused ring group formed by these 5- or 6-memberedaromatic ring groups liked with each other or these 5- or 6-memberedaromatic ring groups linked with a benzene ring (preferably bicyclicfused ring group); and the like are used.

As the “aromatic ring group” of the “aromatic ring group optionallyhaving substituents” for Ar¹ and the “aromatic ring group” of the“aromatic ring group having substituents” for Ar², a 5- or 6-memberedaromatic ring group is preferably used for each of them. Particularly,phenyl group, pyridyl group, thienyl group, furyl group, thiazolyl groupand the like are preferably used.

In the aforementioned formulas, Ar^(2′) denotes an aromatic ring groupoptionally having substituents.

As the “aromatic ring group optionally having substituents” for Ar^(2′),those similar to the “aromatic ring group” of the “aromatic ring grouphaving substituents” for Ar² and “aromatic ring group havingsubstituents” for Ar² and the like are mentioned.

In the aforementioned formulas, R denotes an acyl group. The “acylgroup” may be any of the aforementioned groups, such as acyl groupobtained by removing an OH group from carboxylic acid (e.g., R^(1N)COOH,R^(1N)OCOOH and the like), sulfonic acid (e.g., R^(1N)SO₃H and thelike), sulfinic acid (e.g., R^(1N)SO₂H and the like), phosphoric acid(e.g., R^(1N)OPO(OR^(2N))OH and the like), carbamic acid (e.g.,R^(1N)N(R^(2N))COOH and the like wherein R^(1N) denotes a hydrocarbongroup optionally having substituents or a heterocyclic group optionallyhaving substituents and R^(2N) denotes a hydrogen atom or a hydrocarbongroup optionally having substituents) and the like. Specifically,R^(1N)CO, R^(1N)OCO, R^(1N)SO₂, R^(1N)SO, R^(1N)OPO(OR^(2N)),R^(1N)N(R^(2N))CO (R^(1N) denotes a hydrocarbon group optionally havingsubstituents or a heterocyclic group optionally having substituents andR^(2N) denotes a hydrogen atom or a hydrocarbon group optionally havingsubstituents), and the like are used. Here, as the “hydrocarbon groupoptionally having substituents” denoted by R^(1N), the “heterocyclicgroup optionally having substituents” denoted by R^(1N) and the“hydrocarbon group optionally having substituents” denoted by R^(2N),those similar to “hydrocarbon group optionally having substituents”denoted by the aforementioned R¹, the “heterocyclic group optionallyhaving substituents” denoted by the aforementioned R¹ and the“hydrocarbon group optionally having substituents” denoted by theaforementioned R² are used, respectively.

As R, a group represented by the formula R^(1N)CO— (R^(1N) is ahydrocarbon group optionally having substituents or a heterocyclic groupoptionally having substituents) is preferably used. As R^(1N), a cyclicgroup such as cyclic hydrocarbon group optionally having substituents(e.g., cycloalkyl group optionally having substituents, cycloalkenylgroup optionally having substituents, aryl group optionally havingsubstituents and the like), a heterocyclic group optionally havingsubstituents and the like are preferable. Particularly, an aromatic ringgroup optionally having substituents (a group similar to the “aromaticring group optionally having substituents” for Ar¹ and the like), suchas aryl group optionally having substituents, heteroaryl groupoptionally having substituents and the like are preferably used.

Specifically, as R, C₁₋₆ alkoxy-carbonyl, C₁₋₆ alkyl-carbonyl, C₆₋₁₀aryl-carbonyl (e.g., benzoyl, naphthoyl and the like),dihydronaphthalenecarbonyl, tetrahydronaphthalenecarbonyl,benzocycloheptenecarbonyl (preferably benzo[a]cycloheptene-carbonyl andthe like), benzocyclooctenecarbonyl, each of which may have 1 to 3substituents selected from halogen atom, optionally halogenated C₁₋₆alkoxy, optionally halogenated C₁₋₆ alkyl and the like, are preferable.

In the aforementioned formulas, OR″ denotes an optionally protectedhydroxyl group. Here, R″ denotes a protecting group of hydrogen atom orhydroxyl group (R″ is preferably hydrogen atom or acyl group). As thehydroxyl-protecting group, for example, acyl group, C₁₋₆ alkyloptionally having substituents, phenyl optionally having substituents,C₇₋₁₀ aralkyl optionally having substituents, pyranyl optionally havingsubstituents, furanyl-optionally having substituents, silyl optionallyhaving substituents and the like are mentioned.

The acyl group as the “hydroxyl-protecting group” denoted by R″ may beany mentioned above, and acyl group obtained by removing OH group fromcarboxylic acid such as R^(1O)COOH, R^(1O)OCOOH and the like, sulfonicacid such as R^(1O)SO₃H and the like, sulfinic acid such as R^(1O)SO₂Hand the like, phosphoric acid such as R^(1O)OPO(OR^(2O))OH and the like,carbamic acid such as R^(1O)N(R^(2O))COOH and the like (R^(1O) is ahydrocarbon group optionally having substituents or a heterocyclic groupoptionally having substituents and R^(2O) is a hydrogen atom or ahydrocarbon group optionally having substituents) and the like are used.Specifically, R^(1O)CO, R^(1O)OCO, R^(1O)SO₂, R^(1O)SO,R^(1O)OPO(OR^(2O)), R^(1O)N(R^(2O))CO (R^(1O) denotes a hydrocarbongroup optionally having substituents or a heterocyclic group optionallyhaving substituents and R^(2O) denotes a hydrogen atom or a hydrocarbongroup optionally having substituents) and the like are used. Here, the“hydrocarbon group optionally having substituents” denoted by R^(1O),the “heterocyclic group optionally having substituents” denoted byR^(1O) and the “hydrocarbon group optionally having substituents”denoted by R^(2O), those similar to “hydrocarbon group optionally havingsubstituents” denoted by the aforementioned R¹, “heterocyclic groupoptionally having substituents” denoted by the aforementioned R¹ and“hydrocarbon group optionally having substituents” denoted by theaforementioned R² are used.

As the “acyl group” of the “hydroxyl-protecting group” denoted by R″, agroup represented by the formula R^(1O)CO— (R^(1O) is a hydrocarbongroup optionally having substituents or a heterocyclic group optionallyhaving substituents) is preferably used. As the R^(1O), chainhydrocarbon group optionally having substituents (e.g., alkyl groupoptionally having substituents, alkenyl group optionally havingsubstituents, alkynyl group optionally having substituents and the like)and the like are preferable. Of these, alkyl group optionally havingsubstituents and the like is preferable, and particularly, alkyl grouphaving substituents (e.g., C₁₋₆ alkyl group having 1 to 3 substituentsselected from halogen atom, C₁₋₄ alkoxy group, hydroxy group, C₁₋₄alkoxy-carbonyl group, carboxyl group, carbamoyl group, mono- or di-C₁₋₄alkylcarbamoyl group, amino group, mono- or di-C₁₋₄ alkylamino group,pyridylthio group etc., and the like) and the like are preferably used.

As the “C₁₋₆ alkyl group” of the “C₁₋₆ alkyl group optionally havingsubstituents” as the “hydroxyl-protecting group” denoted by R″, forexample, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and thelike are mentioned, wherein the “C₁₋₆ alkyl group” may have about 1 to 4substituents such as halogen atom (e.g., fluoro, chloro, bromo, iodo andthe like), phenyl, C₇₋₁₀ aralkyl, nitro group and the like.

As the substituent that the “phenyl group” of the “phenyl groupoptionally having substituents” as the “hydroxyl-protecting group”denoted by R″ may have, for example, halogen atom (e.g., fluoro, chloro,bromo, iodo and the like), C₁₋₆ alkyl, phenyl, C₇₋₁₀ aralkyl, nitrogroup and the like are used, wherein the number of substituents is about1 to 4.

As the “C₇₋₁₀ aralkyl” of the “C₇₋₁₀ aralkyl optionally havingsubstituents” as the “hydroxyl-protecting group” denoted by R″, forexample, benzyl and the like can be mentioned. As the substituent thatthe “C₇₋₁₀ aralkyl” may have, for example, halogen atom (e.g., fluoro,chloro, bromo, iodo and the like), C₁₋₆ alkyl, phenyl, C₇₋₁₀ aralkyl,nitro group and the like are used, wherein the number of substituents isabout 1 to 4.

As the substituent that the “pyranyl group” of the “pyranyl groupoptionally having substituents” as the “hydroxyl-protecting group”denoted by R″ may have, for example, halogen atom (e.g., fluoro, chloro,bromo, iodo and the like), C₁₋₆ alkyl, phenyl, C₇₋₁₀ aralkyl, nitrogroup and the like are used, wherein the number of substituents is about1 to 4.

As the substituent that the “furanyl group” of the “furanyl groupoptionally having substituents” as the “hydroxyl-protecting group”denoted by R″ may have, for example, halogen atom (e.g., fluoro, chloro,bromo, iodo and the like), C₁₋₆ alkyl, phenyl, C₇₋₁₀ aralkyl, nitrogroup and the like are used, wherein the number of substituents is about1 to 4.

As the substituent that the “silyl group” of the “silyl group optionallyhaving substituents” as the “hydroxyl-protecting group” denoted by R″may have, for example, C₁₋₆ alkyl, phenyl, C₇₋₁₀ aralkyl and the likeare used, wherein the number of substituents is about 1 to 4.

As the R″, hydrogen atom and the like are preferably used.

In the aforementioned formulas, R′ denotes a hydrogen atom or ahydrocarbon group optionally having substituents. As the R′, hydrogenatom, lower alkyl group optionally having substituents (preferably C₁₋₆alkyl group optionally having 1 to 3 substituents selected from halogenatom, C₁₋₄ alkoxy group, hydroxy group, C₁₋₄ alkoxy-carbonyl group,carboxyl group, carbamoyl group, mono- or di-C₁₋₄ alkylcarbamoyl groupand pyridylthio group and the like) and the like are preferable,hydrogen atom, C₁₋₆ alkyl group and the like are more preferable, andhydrogen atom is particularly preferably used.

As the compound represented by the aforementioned formula (I) or a saltthereof,

-   a compound wherein R is a group represented by the formula R^(1N)CO—    (R^(1N) is a cyclic hydrocarbon group optionally having substituents    or a heterocyclic group optionally having substituents), R″ is a    hydrogen atom, and R′ is a hydrogen atom, or a salt thereof;-   a compound wherein Ar¹ is a 5- or 6-membered aromatic ring group    optionally having substituents selected from halogen atom, an    optionally halogenated lower alkyl group, an optionally halogenated    lower alkoxy group and an aryloxy group optionally having    substituents (e.g., phenyl group, pyridyl group, thienyl group,    furyl group, thiazolyl group and the like; preferably phenyl group    and the like), Ar² is a 5- or 6-membered aromatic ring group having    substituents selected from halogen atom, an optionally halogenated    lower alkyl group and an optionally halogenated lower alkoxy group    (e.g., phenyl group, pyridyl group, thienyl group, furyl group,    thiazolyl group and the like; preferably phenyl group and the like),    R is C₁₋₆ alkoxy-carbonyl, C₁₋₆ alkyl-carbonyl, C₆₋₁₀ aryl-carbonyl    or benzo[a]cycloheptene-carbonyl, each of which may have a    substituent selected from halogen atom, optionally halogenated C₁₋₆    alkoxy and optionally halogenated C₁₋₆ alkyl, R″ is a hydrogen atom,    and R′ is a hydrogen atom, or a salt thereof; and the like are    preferably used.

Since a compound represented by the formula (I) or the formula (I′)

wherein each symbol is as defined above, has at least two asymmetriccarbons, at least 4 optically active forms are present based on theseasymmetric carbons. Each of the active forms and optional mixturesthereof are also encompassed in the compound represented by the formula(I).

In addition, as the compound represented by the formula (I) and theformula (I′), compounds represented by the formulas

wherein each symbol is as defined above, are preferably used.

As the salt of the compound represented by the formula (I) or theformula (I′) of present invention, a salt acceptable as a pharmaceuticalproduct or physiologically acceptable acid addition salt is preferable.As such salt, for example, inorganic acids (e.g., hydrochloric acid,phosphoric acid, hydrobromic acid, sulfuric acid and the like) ororganic acids (e.g., acetic acid, formic acid, propionic acid, fumaricacid, maleic acid, succinic acid, tartaric acid, citric acid, malicacid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonicacid and the like) and the like are used. When the compound representedby the formula (I) of the present invention has an acidic group such ascarboxylic acid and the like, a compound represented by the formula (I)may form a salt with, for example, an inorganic base (e.g., alkali metalor alkaline earth metal such as sodium, potassium, calcium, magnesiumand the like, or ammonia and the like) or an organic base (e.g.,tri-C₁₋₃ alkylamine such as triethylamine etc., and the like).

While salts similar to those mentioned above are used as the startingcompound of a compound represented by the formula (I) of the presentinvention, they are not particularly limited as long as the reaction isnot prohibited.

A prodrug of a compound represented by the formula (I) or a salt thereof[hereinafter sometimes to be referred to as Compound (I)] refers to acompound which is converted to Compound (I) as a result of a reactionwith an enzyme, gastric acid etc. under physiological conditions invivo, thus a compound that undergoes enzymatic oxidation, reduction,hydrolysis etc. to convert into Compound (I) and a compound thatundergoes hydrolysis and the like by gastric acid etc. to convert intoCompound (I). As a prodrug for Compound (I), a compound obtained bysubjecting an amino group in Compound (I) to an acylation, alkylation orphosphorylation (e.g., a compound obtained by subjecting an amino groupin Compound (I) to an eicosanoylation, alanylation,pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, ivaloyloxymethylation,tert-butylation, etc.); a compound obtained by subjecting a hydroxygroup in Compound (I) to an acylation, alkylation, phosphorylation andboration (e.g., a compound obtained by subjecting a hydroxy group inCompound (I) to an acetylation, palmitoylation, propanoylation,pivaloylation, succinylation, fumarylation, alanylation,dimethylaminomethylcarbonylation, etc.); a compound obtained bysubjecting a carboxyl group in Compound (I) to an esterification oramidation (e.g., a compound obtained by subjecting a carboxyl group inCompound (I) to an ethylesterification, phenylesterification,carboxymethylesterification, dimethylamino-methylesterification,pivaloyloxymethylesterification, ethoxycarbonyloxyethylesterification,phthalidylesterification,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification,cyclohexyloxycarbonylethylesterification and methylamidation, etc.) andthe like can be mentioned. Any of these compounds can be produced fromCompound (I) by a method known per se.

A prodrug for Compound (I) may also be one which is converted toCompound (I) under physiological conditions as described in “IYAKUHIN noKAIHATSU (Development of Pharmaceuticals)”, Vol. 7, Design of Molecules,p. 163-198, Published by HIROKAWA SHOTEN (1990).

As a prodrug of a compound represented by the formula (I′) or a saltthereof [hereinafter sometimes to be referred to as Compound (I′)], onesimilar to the prodrug of Compound (I) can be mentioned.

The Compound (I) and Compound (I′) may be a hydrate.

When an optically active form of Compound (I) or Compound (I′) isnecessary, for example, it can be obtained using an optically activestarting material or by resolution of a racemate of the compound by aconventional method.

Preferable examples of Compound (I) of the present invention are shownin the following.

-   N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,-   4-fluoro-N-((1R,2S)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide,-   N-[(1R,2S)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,-   N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2    2-tetrafluoroethoxy)benzyl]ethyl]-5,6-dihydronaphthalene-1-carboxamide,-   N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-1-carboxamide,-   4-fluoro-N-[(1R,2S)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]naphthalene-1-carboxamide,-   N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-5,6,7,8-tetrahydrobenzo[a]cyclooctene-1-carboxamide,-   N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-(4-isopropylbenzyl)ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,-   N-((1RS,2SR)-2-(3-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,-   N-((1RS,2SR)-2-hydroxy-2-(4-phenoxyphenyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,-   N-[(1RS,2SR)-2-(4-chlorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,-   N-((1RS,2SR)-2-hydroxy-2-(4-(phenyloxy)phenyl)-1-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,-   N-((1RS,2SR)-2-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-2-hydroxy-1-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,-   N-((1RS,2SR)-2-(2-fluoropyridin-4-yl)-2-hydroxy-1-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,-   N-((1RS,2RS)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,-   N-[(1RS,2SR)-1-(4-tert-butylbenzyl)-2-(3-chlorophenyl)-2-hydroxyethyl]-5-chloro-1-naphthamide,-   4-fluoro-N-{(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]ethyl}-1-naphthamide,    salts thereof and the like.

The synthetic method of Compound (I) of the present invention isdescribed in the following. In each synthetic method in the following, astarting compound capable of forming a salt may be used in the form of asalt. While such salt is not particularly limited, for example, thesalts such as those mentioned for the aforementioned Compound (I) areused.

In Compound (I) of the present invention, Compound (Ia) wherein R″ is ahydrogen atom can be synthesized by, for example, the following methodand the like.

wherein the symbols in the formula are as defined above.

In this method, Compound (II) is acylated to give Compound (I).

The reaction for converting Compound (II) to Compound (I) is known perse, and can be carried out according to or by referring to theconditions described or cited in, for example, 4th ed. Jikken KagakuKoza (Maruzen) vol. 22, Organic Synthesis IV, pp. 138-151, pp. 259-271,vol. 24, Organic Synthesis VI, pp. 391-392, pp. 396-397 and the like.

In Compound (I), Compound (Ia) wherein R″ is a hydrogen atom can beconverted to Compound (Ib) wherein R″ is a hydroxyl-protecting group bysubjecting Compound (Ia) to a protecting reaction of hydroxyl group.When R″ is an acyl group, for example, a method according to this methodcan afford the conversion.

The reaction for introducing a protecting group into the hydroxyl groupis known per se or a method analogous thereto can be used. The reactioncan be carried out according to or by referring to the conditionsdescribed or cited in, for example, “PROTECTIVE GROUPS IN ORGANICSYNTHESIS” Second Edition (JOHN WILEY & SONS, INC.) pp. 10-142 and thelike.

wherein the symbols in the formula are as defined above.

For reduction reaction of Compound (III), a method comprising use of areducing agent with Compound (III), catalytic hydrogenation in thepresence of a catalyst, electrolytic reduction using lead or platinum asa negative electrode, and the like can be used. As a reducing agent,metal hydrogen complex compounds such as sodium borohydride, sodiumcyanoborohydride, lithium aluminum hydride, zinc borohydride and thelike, diborane and the like can be mentioned. The reducing agent is usedin a monoequivalent amount or large excess (preferably 1-10equivalents). As the catalyst to be used for hydrogenation, metals suchas palladium, platinum, nickel, rhodium and the like, oxides, salts andcomplexes of thereof, and the like can be mentioned. These catalysts canbe also used by being carried on various carriers such as carbon and thelike. The hydrogenation can be conducted under normal pressure or underpressurization. The solvent to be used therefor can be appropriatelydetermined depending on the kind of the reducing agent. For example,alcohols (e.g., methanol, ethanol and the like), ethers (e.g.,tetrahydrofuran, dioxane, diethyl ether and the like), halogenatedhydrocarbon (e.g., methylene chloride, chloroform and the like), aproticpolar solvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide and thelike) and the like can be mentioned. In the reduction using a reducingagent, a catalytic amount or large excess (preferably 0.1-2 equivalents)of a metal halide such as zinc chloride, manganese chloride, aluminumchloride, magnesium chloride and the like may be added to control thereaction. The reaction time is 0.5-72 hrs., preferably 1-24 hrs. Thereaction temperature is from −100° C. to 100° C. (preferably −80° C. to50° C.).

Compound (II) can be synthesized according to, for example, thefollowing method.(i) When R′ is a hydrogen atom

wherein R³, R⁴ and R⁵ are each a C₁₋₆ alkyl optionally havingsubstituents, a C₇₋₁₀ aralkyl optionally having substituents or a C₇₋₁₆aralkyl optionally having substituents, M is a metal atom such assodium, magnesium and the like (in the case of a divalent metal, theremaining monovalent may be occupied by halogen atom and the like), M′is a hydrogen atom or a metal atom such as sodium, magnesium and thelike (in the case of a divalent metal, the remaining monovalent may beoccupied by halogen atom and the like), other symbols are as definedabove.

In this method, Compound (IV) is reacted with Ar²CH₂-M, the resultingimine or iminium ion (V) is reduced and silyl ether is deprotected withan acid to give Compound (II′). In this reaction, Ar²CH₂-M is used in amonoequivalent amount or large excess (preferably 1-10 equivalents)relative to Compound (IV). For the subsequent reduction reaction, amethod comprising use of a reducing agent, catalytic hydrogenation inthe presence of a catalyst, electrolytic reduction using lead orplatinum as a negative electrode, and the like can be used. As areducing agent, metal hydrogen complex compounds such as sodiumborohydride, sodium cyanoborohydride, lithium aluminum hydride, zincborohydride and the like, diborane and the like can be mentioned. Thereducing agent is used in a monoequivalent amount or large excess(preferably 1-10 equivalents). As the catalyst to be used forhydrogenation, metals such as palladium, platinum, nickel, rhodium andthe like, oxides, salts and complexes of thereof, and the like can bementioned. These catalysts can be also used by being carried on variouscarriers such as carbon and the like. The hydrogenation can be conductedunder normal pressure or under pressurization. As the solvent to be usedtherefor, for example, ethers (e.g., tetrahydrofuran, dioxane, diethylether and the like), hydrocarbon (e.g., toluene, hexane and the like),halogenated hydrocarbon (e.g., methylene chloride, chloroform and thelike) and the like can be mentioned. The reaction time is 0.5-72 hrs.,preferably 1-24 hrs. The reaction temperature is from −100° C. to 100°C. (preferably −80° C. to 50° C.). After the reduction reaction, anaqueous solution of an acid such as hydrochloric acid, sulfuric acid,acetic acid and the like is added to the reaction mixture to removesilyl ether, whereby Compound (II′) can be obtained.

wherein D is an amino-protecting group such as tert-butoxycarbonyl,benzyloxycarbonyl, acetyl, trifluoroacetyl, benzyl and the like, andother symbols are as defined above.

In this method, the amino-protecting group of compound (VI) is removedto give Compound (II). The reaction for removing amino-protecting groupis known per se, and can be carried out according to such conditions.

wherein the symbols in the formula are as defined above.

The reaction for converting Compound (VII) to Compound (II) is carriedout in the presence of a monoequivalent amount or large excess of anaqueous solution of a metal hydroxide such as sodium hydroxide,potassium hydride and the like, an aqueous solution of an acid such ashydrochloric acid, sulfuric acid and the like, trimethylsilyl iodide andthe like. As the solvent to be used therefor, for example, water,alcohols (e.g., methanol, ethanol and the like), ethers (e.g.,tetrahydrofuran, dioxane, diethyl ether and the like), halogenatedhydrocarbons (e.g., methylene chloride, chloroform and the like),ketones (e.g., acetone, methyl ethyl ketone and the like), aprotic polarsolvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide and the like)and the like can be mentioned. The reaction time is 10 min.-24 hrs. andthe reaction temperature is from −20° C. to 200° C. (preferably 0° C. to100° C.).

Compound (III) can be synthesized by, for example, the following method.

wherein the symbols in the formula are as defined above.

The reaction for converting Compound (VIII) to Compound (III) is carriedout under the same conditions as, for example, the method under (i) inthe synthesis of Compound (I).

Compound (IV) can be synthesized by, for example, the following method.

wherein the symbols in the formula are as defined above.

The reaction for converting Compound (IX) to Compound (IV) is known perse, and can be carried out according to or y referring to the conditionsdescribed or cited in, for example, Tetrahedron Lett., 26, 4275-4278(1985), J. Org. Chem., 51, 413-415 (1986), Tetrahedron Lett., 28,5513-5516 (1987), Chem. Lett., 537-540 (1991), J. Chem. Soc. Chem. Comm.1752-1753 (1991), J. Org. Chem., 55, 1479-1483 (1990), J. FluorineChem., 35, 287-294 (1987), Tetrahedron Lett., 33, 2159-2162 (1992),Tetrahedron Lett., 34, 4001-4004 (1992) and the like.

Compound (VI) can be synthesized by, for example, the following method.

wherein the symbols in the formula are as defined above.

The reaction for converting Compound (X) to Compound (VI) is carried outunder the same conditions as, for example, the method under (ii) in thesynthesis of Compound (I).(ii) when R′ is a hydrogen atom

wherein the symbols in the formula are as defined above.

The reaction for converting Compound (XI) to Compound (VI′) is carriedout under the same conditions as, for example, the method under (iii) inthe synthesis of Compound (II).

Compound (VII) wherein R′ is not a hydrogen atom can be synthesizedaccording to, for example, the following method.

wherein the symbols in the formula are as defined above.

In this method, Compound (VII′) is reacted with an alkylation agent togive Compound (VII). In this reaction, alkylation agent is used in amonoequivalent amount or large excess (preferably 1-10 equivalents)relative to compound (VII′). In this case, for example, 1-10 equivalentsof a basic compound such as sodium hydroxide, potassium hydroxide,sodium hydride, potassium carbonate, triethylamine,diisopropylethylamine, pyridine, 4-N,N-dimethylaminopyridine (DMAP),1,8-diazabicyclo[5.4.0]-7-undecene, 1,4-diazabicyclo[2.2.2]octane(DABCO) and the like may be used. As the alkylation agent to be used,halogenated hydrocarbon, sulfonic acid esters such as alkylmethanesulfonate, alkyl p-toluenesulfonate and the like, and the likecan be mentioned. For this reaction, an alkali metal iodide such assodium iodide and the like can be added in a monoequivalent amount orlarge-excess (preferably 1-10 equivalents) as a reaction promoter. Asthe solvent to be used therefor, for example, water, alcohols (e.g.,methanol, ethanol and the like), ethers (e.g., tetrahydrofuran, dioxane,diethyl ether and the like), halogenated hydrocarbon (e.g., methylenechloride, chloroform and the like), ketones (e.g., acetone, methyl ethylketone and the like), aprotic polar solvents (e.g.,N,N-dimethylformamide, dimethyl sulfoxide and the like) and the like canbe mentioned. The reaction time is 10 min-24 hrs., preferably 0.5-6hrs., and the reaction temperature is from −20° C. to 200° C.(preferably 0° C. to 150° C.).

Compound (VII′) (compound (VII) wherein R′ is a hydrogen atom) can besynthesized according to, for example, the following method.

wherein the symbols in the formula are as defined above.

In this method, carboxyl group of Compound (XII) is converted to acylazide, which is then led to isocyanate using what is called a Curtiusrearrangement reaction, and the resulting isocyanate is cyclized with ahydroxyl group in the molecule to give Compound (VII′). During thereaction, acyl azide can be synthesized by, for example, the followingthree methods.

-   Method A: Compound (XII) is treated with a monoequivalent amount or    large excess of a halogenation agent (e.g., thionyl chloride, oxalyl    chloride, phosphorus pentachloride and the like) to convert the    compound to acyl halide. In this reaction, a basic compound such as    pyridine, 4-N,N-dimethylaminopyridine, triethylamine and the like    may be used in 1-10 equivalents. In this reaction, a catalytic    amount of N,N-dimethylformamide may be added as a reaction promoter.    As the solvent to be used therefor, for example, ethers (e.g.,    tetrahydrofuran, dioxane, diethyl ether and the like), halogenated    hydrocarbons (e.g., methylene chloride, chloroform and the like),    ketones (e.g., acetone, methyl ethyl ketone and the like), esters    (e.g., ethyl acetate and the like), aprotic polar solvents (e.g.,    N,N-dimethylformamide, dimethyl sulfoxide and the like) and the like    can be mentioned. The reaction temperature is from −100° C. to    200° C. (preferably −20° C. to 100° C.). The obtained acyl halide is    reacted with a monoequivalent amount or large excess of alkali metal    azide salt (e.g., sodium azide and the like) to give acyl azide. In    this reaction, a basic compound such as pyridine,    4-N,N-dimethylaminopyridine, triethylamine and the like may be used    in 1-10 equivalent amount. As the solvent to be used therefor, for    example, ethers (e.g., tetrahydrofuran, dioxane, diethyl ether and    the like), halogenated hydrocarbons (e.g., methylene chloride,    chloroform and the like), ketones (e.g., acetone, methyl ethyl    ketone and the like), esters (e.g., ethyl acetate, and the like),    aprotic polar solvents (e.g., N,N-dimethylformamide, dimethyl    sulfoxide and the like) and the like can be mentioned. The reaction    temperature is from −100° C. to 200° C. (preferably −20° C. to 100°    C.).-   Method B: After conversion of Compound (XII) to acyl halide    according to Method A, acyl halide-is treated with a monoequivalent    amount or large excess of hydrazine to give hydrazide. In this    reaction, a basic compound such as pyridine,    4-N,N-dimethylaminopyridine, triethylamine and the like may be used    in 1-10 equivalent amount. As the solvent to be used therefor, for    example, ethers (e.g., tetrahydrofuran, dioxane, diethyl ether and    the like), halogenated hydrocarbons (e.g., methylene chloride,    chloroform and the like), ketones (e.g., acetone, methyl ethyl    ketone and the like), esters (e.g., ethyl acetate and the like),    aprotic polar solvents (e.g., N,N-dimethylformamide, dimethyl    sulfoxide and the like) and the like can be mentioned. The reaction    temperature is from −100° C. to 200° C. (preferably −20° C. to 100°    C.). The obtained hydrazide is treated with a monoequivalent amount    or large excess of nitrous acid (which can be also generated from    metal nitrites such as sodium nitrite and the like in the presence    of an acid) to give acyl azide. As the solvent to be used therefor,    for example, water, alcohols (e.g., methanol, ethanol and the like),    ethers (e.g., tetrahydrofuran, dioxane, diethyl ether and the like),    halogenated hydrocarbon (e.g., methylene chloride, chloroform and    the like), ketones (e.g., acetone, methyl ethyl ketone and the    like), esters (e.g., ethyl acetate and the like), aprotic polar    solvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide and the    like) and the like can be mentioned. The reaction temperature is    from −100° C. to 200° C. (preferably −20° C. to 50° C.).-   Method C: Compound (XII) is reacted with a monoequivalent amount or    large excess of diphenylphosphoryl azide to give acyl azide. In this    case, for example, 1-10 equivalents of a basic compound such as    sodium hydroxide, potassium hydroxide, sodium hydride, potassium    carbonate, triethylamine, diisopropylethylamine, pyridine,    4-N,N-dimethylaminopyridine (DMAP)    1,8-diazabicyclo[5.4.0]-7-undecene, 1,4-diazabicyclo[2.2.2]octane    (DABCO) and the like may be used. As the solvent to be used    therefor, for example, water, alcohols (e.g., methanol, ethanol and    the like), ethers (e.g., tetrahydrofuran, dioxane, diethyl ether and    the like), halogenated hydrocarbons (e.g., methylene chloride,    chloroform and the like), ketones (e.g., acetone, methyl ethyl    ketone and the like), esters (e.g., ethyl acetate and the like),    aprotic polar solvents (e.g., N,N-dimethylformamide, dimethyl    sulfoxide and the like) and the like can be mentioned. The reaction    time is 10 min-24 hrs., preferably 0.5-6 hrs. and the reaction    temperature is from −20° C. to 200° C.

The obtained acyl azide is subjected to a Curtius rearrangement reactionto lead to isocyanate. This reaction is carried out by heating theobtained acyl azide from 30° C. to 200° C. In this case, for example,1-10 equivalents of a basic compound such as triethylamine,diisopropylethylamine, pyridine, 4-N,N-dimethylaminopyridine (DMAP),1,8-diazabicyclo[5.4.0]-7-undecene, 1,4-diazabicyclo[2.2.2]octane(DABCO) and the like may be used. The reaction can be also carried outin a solvent such as water, alcohols (e.g., methanol, ethanol and thelike), ethers (e.g., tetrahydrofuran, dioxane, diethyl ether and thelike), halogenated hydrocarbons (e.g., methylene chloride, chloroformand the like), ketones (e.g., acetone, methyl ethyl ketone and thelike), esters (e.g., ethyl acetate and the like), aprotic polar solvents(e.g., N,N-dimethylformamide, dimethyl sulfoxide and the like) and thelike. The reaction time is 10 min-24 hrs., preferably 0.5-6 hrs. It isalso possible to carry out an intramolecular cyclization reactionsubsequent to the Curtius reaction under these reaction conditions inthe same system to lead to Compound (VII′).

The reaction to introduce isocyanate obtained by Curtius reaction toCompound (VII′) is conducted by heating the isocyanate from 30° C. to200° C. In this case, for example, 1-10 equivalents of a basic compoundsuch as triethylamine, diisopropylethylamine, pyridine,4-N,N-dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]-7-undecene,1,4-diazabicyclo[2.2.2]octane (DABCO) and the like may be used. Thereaction can be also carried out in a solvent such as water, alcohols(e.g., methanol, ethanol and the like), ethers (e.g., tetrahydrofuran,dioxane, diethyl ether and the like), halogenated hydrocarbons (e.g.,methylene chloride, chloroform and the like), ketones (e.g., acetone,methyl ethyl ketone and the like), esters (e.g., ethyl acetate and thelike), aprotic polar solvents (e.g., N,N-dimethylformamide, dimethylsulfoxide and the like) and the like. The reaction time is 10 min-24hrs., preferably 0.5-6 hrs.

The series of reactions from Compound (XII) to Compound (VII′) can bealso carried out in the same system without isolation of eachintermediate.

Compound (VIII) can be synthesized by, for example, the followingmethod.

wherein the symbols in the formula are as defined above.

The reaction for converting Compound (X) to Compound (VIII) is carriedout under the same conditions as, for example, the method under (ii) inthe synthesis of Compound (II).

Compound (X) wherein R′ is not a hydrogen atom can be synthesized by,for example, the following method.

wherein the symbols in the formula are as defined above.

The reaction for converting Compound (X′) to Compound (X) is carried outunder the same conditions as, for example, the method for the synthesisof Compound (VII).

Compound (X′) (compound (X) wherein R′ is a hydrogen atom) can besynthesized by, for example, the following method.

wherein E is a leaving group such as halogen atom (e.g., chloro, bromo,iodo and the like), methanesulfonyloxy, p-toluenesulfonyloxy and thelike, and other symbols are as defined above.

In this reaction, Compound (XIII) is reacted with Ar²CH₂-E in thepresence of a basic compound to give Compound (X′). In this reaction, amonoequivalent amount or large excess of basic compound and amonoequivalent amount or large excess of Ar²CH₂-E, relative to Compound(XIII), are used. As the basic compound to be used in this case, forexample, sodium hydroxide, potassium hydroxide, sodium hydride,potassium carbonate, triethylamine, diisopropylethylamine, pyridine,4-N,N-dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]-7-undecene,1,4-diazabicyclo[2.2.2]octane (DABCO) and the like can be mentioned. Asthe solvent to be used therefor, for example, water, alcohols (e.g.,methanol, ethanol and the like), ethers (e.g., tetrahydrofuran, dioxane,diethyl ether and the like), halogenated hydrocarbons (e.g., methylenechloride, chloroform and the like), ketones (e.g., acetone, methyl ethylketone and the like), esters (e.g., ethyl acetate and the like), aproticpolar solvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide and thelike) and the like can be mentioned. The reaction time is 10 min-24hrs., preferably 0.5-6 hrs. The reaction temperature is from −20° C. to200° C. (preferably 0° C. to 80° C.).

Compound (XI) can be synthesized by, for example, the following method.

wherein the symbols in the formula are as defined above.

In this reaction, Compound (VII′) is reacted with a reagent to introducean amino-protecting group in the presence of a basic compound to giveCompound (XI). In this reaction, a monoequivalent amount or large excessof basic compound and a monoequivalent amount or large excess of areagent to introduce an amino-protecting group, relative to Compound(VII′), are used. As the basic compound to be used in this case, forexample, sodium hydroxide, potassium hydroxide, sodium hydride,potassium carbonate, triethylamine, diisopropylethylamine, pyridine,4-N,N-dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]-7-undecene,1,4-diazabicyclo[2.2.2]octane (DABCO) and the like can be mentioned. Asthe reagent to introduce an amino-protecting group to be used here, forexample, acetic anhydride, trifluoroacetic anhydride, acetic chloride,benzyl chlorocarbonate, di-tert-butyl dicarbonate and the like can bementioned. As the solvent to be used therefor, for example, water,alcohols (e.g., methanol, ethanol and the like), ethers (e.g.,tetrahydrofuran, dioxane, diethyl ether and the like), halogenatedhydrocarbons (e.g., methylene chloride, chloroform and the like),ketones (e.g., acetone, methyl ethyl ketone and the like), esters (e.g.,ethyl acetate and the like), aprotic polar solvents (e.g.,N,N-dimethylformamide, dimethyl sulfoxide and the like) and the like canbe mentioned. The reaction time is 10 min-24 hrs., preferably 0.5-6 hrs.The reaction temperature is from −20° C. to 200° C. (preferably 0° C. to80° C.).

Compound (XII) can be synthesized by, for example, the following method.

wherein R′″ is a C₁₋₆ alkyl optionally having substituents, C₇₋₁₀aralkyl optionally having substituents or C₇₋₁₆ aralkyl optionallyhaving substituents, and other symbols are as defined above.

In this method, an ester group of Compound (XIV) is hydrolyzed to giveCompound (XII). The hydrolysis of ester group is all known per se, andcan be carried out under such conditions.

Compound (XIII) can be synthesized by, for example, the followingmethod.

wherein the symbols in the formula are as defined above.

In this method, a protecting group is introduced into amino group ofCompound (XV) to give Compound (XIII). The reaction for protecting aminogroup with a protecting group is known per se, and can be carried outunder such conditions.

Compound (XIV) can be synthesized by, for example, the following method.

wherein the symbols in the formula are as defined above.

The reaction for converting Compound (XVI) to Compound (XIV) is carriedout under the same conditions as, for example, the method under (ii) inthe synthesis of Compound (I).

Compound (XV) can be synthesized by, for example, the following method.

wherein the symbols in the formula are as defined above.

For reduction reaction of Compound (XVII), catalytic hydrogenation inthe presence of a catalyst and the like can be used. As the catalyst tobe used for hydrogenation, metals such as palladium, platinum, nickel,rhodium and the like, oxides, salts and complexes of thereof, and thelike can be mentioned. These catalysts can be also used by being carriedon various carriers such as carbon and the like. The hydrogenation canbe conducted under normal pressure or under pressurization. The solventto be used therefor can be appropriately determined. For example,alcohols (e.g., methanol, ethanol and the like), ethers (e.g.,tetrahydrofuran, dioxane, diethyl ether and the like), halogenatedhydrocarbons (e.g., methylene chloride, chloroform and the like), esters(e.g., ethyl acetate and the like), aprotic polar solvents (e.g.,N,N-dimethylformamide, dimethyl sulfoxide and the like) and the like canbe mentioned. The reaction time is 0.5-72 hrs., preferably 1-24 hrs. Thereaction temperature is from −100° C. to 100° C. (preferably −70° C. to50° C.).

Compound (XVI) can be synthesized by, for example, the following method.

wherein the symbols in the formula are as defined above.

The reaction for converting Compound (XVIII) to Compound (XVI) iscarried out under the same conditions as, for example, in the method forthe synthesis of Compound (X′). Compound (XVIII), which is a startingcompound, can be synthesized from Ar¹ COOH according to or by referringto the conditions described or cited in, for example, Heterocycles, 23,2277-2287 (1985), J. Org. Chem., 53, 869-873 (1988), J. Org. Chem., 53,873-875 (1986), Chem. Pharm. Bull., 38, 103-109 (1990) and the like;from Ar¹C(═O)Cl according to or by referring to the conditions describedor cited in, for example, J. Am. Chem. Soc., 109, 7488-7494 (1987), J.Org. Chem., 53, 2968-2971 (1988), Tetrahedron Lett., 32, 7731-7734(1991) and the like, and from Ar¹C(═O)CH₃ according to or by referringto the conditions described or cited in, for example, J. HeterocyclicChem., 22, 1033-1034 (1985), J. Heterocyclic Chem., 25, 1737-1740(1988), J. Med. Chem., 34, 798-806 (1991), Tetrahedron, 46, 4473-4486(1990), J. Org. Chem., 64, 1512-1519 (1999) and the like.

Compound (XVII) can be synthesized by, for example, the followingmethod.

wherein X is a halogen atom, and other symbols are as defined above.

In this reaction, Compound (XIX) is reacted with a monoequivalent amountor large excess of alkali metal azide salt (e.g., sodium azide and thelike) to give Compound (XVII). As the solvent to be used therefor, forexample, water, alcohols (e.g., methanol, ethanol and the like), ethers(e.g., tetrahydrofuran, dioxane, diethyl ether and the like),halogenated hydrocarbons (e.g., methylene chloride, chloroform and thelike), ketones (e.g., acetone, methyl ethyl ketone and the like), esters(e.g., ethyl acetate and the like), aprotic polar solvents (e.g.,N,N-dimethylformamide, dimethyl sulfoxide and the like) and the like canbe mentioned. The reaction time is 10 min-24 hrs. and the reactiontemperature is from −20° C. to 200° C. (preferably 0° C. to 50° C.).

In each reaction for the synthesis of the above-mentioned objectivecompounds and-starting compounds, when a starting compound to be usedhas an amino group, a carboxyl group or a hydroxy group as asubstituent, such group may be protected by a protecting group generallyused for peptide chemical synthesis and the like. After the reaction,the protecting group is removed as necessary to give the objectivecompound.

As the amino-protecting group, for example, C₁₋₆ alkylcarbonyl (e.g.,formyl, methylcarbonyl, ethylcarbonyl and the like), phenylcarbonyl,C₁₋₆ alkyl-oxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl and thelike), C₆₋₁₀ aryl-oxycarbonyl (e.g., phenyloxycarbonyl and the like),C₇₋₁₀ aralkyl-carbonyl (e.g., benzyloxycarbonyl and the like), trityl,phthaloyl, each of which may have substituent(s), and the like are used.As the substituent of these, halogen atom (e.g., fluoro, chloro, bromo,iodo and the like), C₁₋₆ alkyl-carbonyl (e.g., methylcarbonyl,ethylcarbonyl, butylcarbonyl and the like), nitro group and the like areused, wherein the number of substituents is about 1 to 3.

As the carboxyl-protecting group, for example, C₁₋₆ alkyl (e.g., methyl,ethyl, propyl, isopropyl, butyl, tert-butyl and the like), phenyl,trityl, silyl, each of which may have substituent(s), and the like areused. As the substituent of these, halogen atom (e.g., fluoro, chloro,bromo, iodo and the like), C₁₋₆ alkylcarbonyl (e.g., formyl,methylcarbonyl, ethylcarbonyl, butylcarbonyl and the like), nitro groupand the like are used, wherein the number of substituents is about 1 to3.

As the hydroxy-protecting group, for example, C₁₋₆ alkyl (e.g., methyl,ethyl, propyl, isopropyl, butyl, tert-butyl and the like), phenyl, C₇₋₁₀aralkyl (e.g., benzyl and the like), C₁₋₆ alkylcarbonyl (e.g., formyl,methylcarbonyl, ethylcarbonyl and the like), C₆₋₁₀ aryl-oxycarbonyl(e.g., phenyloxycarbonyl and the like), C₇₋₁₀ aralkyl-carbonyl (e.g.,benzyloxycarbonyl and the like), pyranyl, furanyl, silyl, each of whichmay have substituent(s), and the like are used. As the substituent ofthese, halogen atom (e.g., fluoro, chloro, bromo, iodo and the like),C₁₋₆ alkyl, phenyl, C₇₋₁₀aralkyl, nitro group and the like are used,wherein the number of substituents is about 1 to 3.

As a method for removing the protecting group, a method known per se ora method analogous thereto are used. For example, there may be usedmethods employing treatment with an acid, a base, reduction, ultravioletrays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate,tetrabutylammonium fluoride, palladium acetate and the like are used.

For separation and purification of Compound (I) from a reaction mixtureand the starting material thereof, a conventional means for separationand purification (e.g., extraction, concentration, filtration,recrystallization, column chromatography, thin layer chromatography) isperformed.

When Compound (I) thus obtained is a free form, it can be converted to asalt by a method known per se or a method analogous thereto (e.g.,neutralization etc.). When it is obtained as a salt, it can be convertedto a free form or other salt by a method known per se or a methodanalogous thereto.

Furthermore, when Compound (I) is an optically active form, it can beresolved into a d-form and an l-form by a conventional means for opticalresolution.

Compound (I) and Compound (I′) of the present invention are low toxic,useful as a pharmaceutical product, and have a cholesteryl estertransfer protein inhibitory action, a superior HDL-cholesterolincreasing action, an LDL-cholesterol lowering action, a VLDLcholesterol lowering action and a triglyceride lowering action.Therefore, the agent of the present invention is useful for theprophylaxis or treatment of diseases based on these pharmacologicalactions. That is, the agent is particularly suitable for the prophylaxisor treatment of the diseases such as hyperlipidemia, particularly highLDL-cholesterolemia, high lipoproteinemia and hypertriglyceridemia, lowHDL-cholesterolemia, aterosclerotic vascular lesion resulting therefromand deuteropathy thereof, acute coronary syndrome such as acute cardiacinfarction, unstable angina pectoris and the like, peripheral arterialocclusion, percutaneous transluminal coronary angioplasty (PTCA) orarterial restenosis after stent placement, ischemic heart disease suchas cardiac infarction, angina pectoris and the like, arteriosclerosis,intermittent claudication, stroke (cerebral infarction, cerebralembolus, cerebral hemorrhage and the like), lacunar infarction,cerebrovascular dementia, gangrene, glomerulosclerosis, nephropathy,Tangier disease and the like, and for the suppression of progression offocal arteriosclerosis and the like, in mammals (e.g., mouse, rat,hamster, rabbit, cat, dog, bovine, horse, sheep, monkey, human etc.).

When Compound (I) and Compound (I′) of the present invention arecompared with a pharmaceutical agent that has an LDL-cholesterollowering action but does not show an HDL-cholesterol increasing action,they are useful for the prophylaxis or treatment of primaryhypo-HDL-emia and the like, for which an LDL-cholesterol lowering actionalone has no treatment effect. The final object of therapeutic agents of10 hyperlipidemia is prevention of the onset of deadly diseases such ascardiac infarction and the like, and even a pharmaceutical agent havingan LDL lowering action but without an HDL increasing action shows anonset-preventive effect to some degree against cardiac infarction andthe like. However, an HDL-cholesterol elevating agent can show strongerprevention of the onset of cardiac infarction and the like. Moreover, itis effective for patients and diseases and conditions (e.g., intractablehyperlipidemia and the like), for which a pharmaceutical agent having anLDL lowering action but without an HDL increasing action fails to show atreatment effect, and even in humans showing a normal level of serumlipid, it suppresses the onset rate of deadly diseases such as cardiacinfarction and the like, thereby improving treatment effects.

While Compound (I) and Compound (I′) can be used as a bulk powder, it isgenerally formulated together with suitable amounts of appropriatelyselected carriers for preparations, such as excipients (e.g., calciumcarbonate, kaolin, sodium hydrogen carbonate, lactose, starches,crystalline cellulose, talc, granulated sugar, porous substance etc.),binders (e.g., dextrin, rubbers, alcoholized starch, gelatin,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, pullulan etc.),disintegrants (e.g., carboxymethyl cellulose calcium, croscarmellosesodium, crospovidone, low substituted hydroxypropyl cellulose, partiallypregelatinized starch etc.), lubricants (e.g., magnesium stearate,calcium stearate, talc, starch, sodium benzoate etc.), coloring agents(e.g., tar dye, caramel, ferric oxide, titanium oxide, riboflavinsetc.), corrigents (e.g., sweeteners, flavoring etc.), stabilizers (e.g.,sodium sulfite etc.) and preservatives (e.g., parabens, sorbic acidetc.) and the like according to a conventional method and administered.The prophylactic or therapeutic agent of the present inventioncontaining the aforementioned preparation appropriately contains aneffective amount of Compound (I) or Compound (I′) for the treatment orprophylaxis of diseases. The content of Compound (I) and Compound (I′)in the preparation of the present invention is generally 0.1 to 100 wt %of the entire preparation. The preparation to be used in the presentinvention may contain a pharmaceutical component other than Compound (I)or Compound (I′) as an active ingredient, wherein the component is notparticularly limited as long as the object of the present invention canbe achieved, and can be used in an appropriately suitable mixing ratio.Examples of the dosage form include tablets (including sugar-coatedtablet and film-coated tablet), pill, capsule, granule, fine granules,powder, syrup, emulsion, suspension, injection, inhalant, ointment andthe like. These preparations can be prepared according to a conventionalmethod (e.g., method described in Japan Pharmacopoeia etc.).

To be specific, tablets can be produced by adding excipient, binder,disintegrant or other suitable additives to Compound (I) or Compound(I′), admixing homogeneously, granulating by a suitable method to givegranules, adding lubricant etc. and compression-forming; or directlycompression-forming Compound (I) or Compound (I′) as it is or ahomogeneous admixture thereof with excipient, binder, disintegrant orother suitable additives; compression-forming granules as they are,which have been prepared in advance or after admixing homogeneously withsuitable additives. In addition, coloring agents, corrigents and thelike can be added to this agent where necessary. Moreover, a film may beformed on this agent with a suitable coating agent. Injection can beproduced by dissolving, suspending or emulsifying a given amount ofCompound (I) or Compound (I′) in water for injection, physiologicalsaline, Ringer solution and the like in the case of aqueous solvents andgenerally in vegetable oil and the like in the case of non-aqueoussolvents to a given amount or sealing a given amount of Compound (I) orCompound (I′) in a vessel for injection.

As the carrier for oral preparation, for example, substancesconventionally used in the field of pharmaceutical preparation, such asstarch, mannitol, crystalline cellulose, carboxymethyl cellulose sodiumand the like, are used. As the carrier for injection, for example,distilled water, physiological saline, glucose solution, transfusion andthe like are used. In addition, additives generally used for preparationcan be added appropriately.

The preparation of the present invention can be also used as a sustainedrelease preparation. As the sustained release preparation of the presentinvention, for example. microcapsule (e.g., microsphere microcapsule,microparticle etc.) produced by in-water drying method (o/w method,w/o/w method etc.), phase separation method, spray drying method or amethod analogous thereto may-be administered as it is or saidmicrocapsule or a pharmaceutical composition in the form of a sphere,needle, pellet, film or cream as a starting material may be preparedinto various dosage forms and administered. As the dosage form, forexample, parenteral agents (e.g., intramuscular injection, subcutaneousinjection, injection into organ etc. or embedded agent; transmucosalagent to nasal cavity, rectum, uterus etc. and the like), oral agent(e.g., hard capsule, soft capsule, granule, powder, suspension etc.) andthe like can be mentioned.

When the sustained release preparation of the present invention is aninjection, microcapsules may be prepared with a dispersing agent (e.g.,surfactant such as Tween 80, HCO-60 and the like; polysaccharides suchas carboxymethyl cellulose, sodium alginate, sodium hyaluronate and thelike; protamine sulfate, polyethylene glycol etc.), preservatives (e.g.,methylparaben, propylparaben etc.), isotonicity agents (e.g., sodiumchloride, mannitol, sorbitol, glucose etc.), local anesthesia (e.g.,xylocaine hydrochloride, chlorobutanol etc.) and the like to give anaqueous suspension, or dispersed together with a vegetable oil. (e.g.,sesame oil, corn oil etc.) or a mixture of vegetable oil andphospholipid (e.g., lecithin etc.), or middle chain fatty acidtriglyceride (e.g., miglyol 812 etc.) to give an oil suspension and usedas a sustained release injection.

When the sustained release preparation of the present invention is amicrocapsule, its average particle size is about 0.1 to about 300 μm,preferably about 1 to about 150 μm, more preferably about 2 to about 100μm.

To give a sterile preparation of microcapsule, there can be mentioned,but not particularly limited to, a method comprising sterilizing all theproduction steps, a method comprising sterilization with gamma rays, amethod comprising addition of preservatives and the like.

For the treatment of these diseases, Compound (I) and Compound (I′) canbe used alone for the prophylaxis and/or treatment or may be used alongwith other pharmaceutical components such as lipid-lowering drugs,cholesterol-lowering drugs, cardiac muscle protective drugs, therapeuticdrugs of coronary diseases, therapeutic drugs of diabetes, therapeuticdrugs of hypothyroidism, therapeutic drugs of nephrotic syndrome,therapeutic drugs of osteoporosis and therapeutic drugs of chronickidney failure. In this case, these compounds are preferablyadministered as an oral preparation, but where necessary, they may beadministered as a rectal preparation in the form of a suppository. As acombinable component in this case, for example, (1) PPAR_(α) agonistssuch as fibrates (e.g., clofibrate, bezafibrate, gemfibrogil,fenofibrate etc.) and the like, nicotinic acid, derivatives thereof andanalogs thereof (e.g., acipimox, probucol etc.), (2) bile acid bindingresin (e.g., colestyramine, colestipol etc.), a compound suppressingabsorption of cholesterol (e.g., sitosterol, neomycin etc.), (3)compound inhibiting biosynthesis of cholesterol (e.g., HMG-CoA reductaseinhibitors such as lovastatin, simvastatin, pravastatin, cerivastatin,atorvastatin, fluvastatin, itavastatin, rosuvastatin and the like),squalene epoxidase inhibitors (e.g., NB-598 and analog compound thereofetc.), squalene synthase inhibitors (e.g., benzoxazepine derivativeetc.) and the like can be mentioned.

Different combinable components are oxide squalene-lanosterol cyclase(e.g., decalin derivative, azadecalin derivative, indan derivativeetc.), microsome triglyceride transfer protein inhibitor (implitapideetc.) and the like.

When combined with a therapeutic drug of diabetes [actos, rosiglitazone,kinedak, penfill, humalin, euglucon, glimicron, daonil, novolin,monotard, insulins, glucobay, dimelin, rastinon, bacilcon, deamelin S,iszilins]; therapeutic drugs of hypothyroidism [dry thyroid (thyreoid),levothyroxine sodium (thyrodin S), liothyronine sodium (thyronine,thyronamin); therapeutic drugs of nephrotic syndrome: prednisolone(predonine), prednisolone sodium succinate (predonine), sodiummethylprednisolone succinate (solu-medrol), betamethasone (rinderon)];anticoagulative therapy drugs [dipyridamole (persantine), dilazephydrochloride (comelian), ticlopidine, clobidogrel, Xa inhibitor];therapeutic drugs of chronic kidney failure [diuretic [e.g., furosemide(lasix), bumetanide (lunetoron), azosemide (diart)], depressor (e.g.,ACE inhibitor, (enalapril maleate (renivase)) and Ca antagonists(manidipine), α receptor blocker, AII antagonists (candesartan)) and thelike for administration, oral administration is preferable.

Furthermore, Compound (I) and Compound (I′) are suitable for thetreatment of diseases associated with excessive cell growth. A mainexample of the diseases associated with excessive cell growth is tumor.It has been reported that tumor growth can be suppressed by loweringserum total cholesterol or LDL-cholesterol or VLDL-cholesterol (Lancet339: 1154-1156, 1992). Therefore, Compound (I) and Compound (I′) cantreat tumor because they have an LDL-cholesterol or VLDL-cholesterollowering action. They can be used for the treatment of tumor bythemselves or in combination with known treatment methods. Otherapplicable diseases include hyperproliferative skin diseases, such aspsoriasis, basal cell cancer, squamous cell carcinoma, keratosis andkeratosis diseases.

The hyperproliferative vascular diseases, such as angiostenosis andocclusion caused by surgical means such as PTCA (percutaneoustransluminal coronary angioplasty) or bypass surgery are based on thegrowth of smooth muscle cells, and the compound of the present inventionis also suitable for the treatment or prophylaxis of these disease inview of its LDL-cholesterol and VLDL-cholesterol lowering action. Forthis end, the compound is used alone or in combination with known activecompound, such as heparin and the like that can be administeredintravenously, preferably given by oral administration.

A further possible use of the compound of the present invention isprophylaxis or treatment of gallstone. When cholesterol in the bile hasexceeded its maximum solubility, cholesterol precipitates to formgallstone. The lipid-lowering drugs of fibrates increase secretion ofneutral steroid into the bile and increases the sensitivity of gallstoneformation. In contrast, cholesterol biosynthesis inhibitors such aslovastatin and pravastatin do not promote gallstone forming, but causelower cholesterol concentration in the bile, which could decrease thegallstone forming index (Gut 31: 348-350, 1990). It has been reportedthat, when combined with ursodeoxycholic acid, lovastatin is effectivefor dissolving gallstone (Gastroenterology 102, No. 4, Pt. 2, A319,1992). In view of the mode of action, therefore, the compound of thepresent invention is suitable for the prophylaxis or treatment ofgallstone. For this end, the compound is used alone or in combinationwith known therapeutic compound (e.g., ursodeoxycholic acid and thelike), or a known treatment method (e.g., shock wave lithotripsy and thelike), and can be administered orally.

Compound (I) and Compound (I′) of the present invention have a bloodHDL-cholesterol increasing action. By the increase in the bloodHDL-cholesterol, export of cholesterol from the cell with excesscholesterol is promoted (Current Opinion in Lipidology 4: 392-400).Thus, the Compounds are suitable for the prophylaxis or treatment ofatherosclerosis. In consideration of biological characteristics thereof,the Compounds are particularly suitable for the prophylaxis or treatmentof atherosclerotic vascular lesion and deuteropathy thereof, such ascoronary disease (CHD), cerebral ischemia, intermittent claudication,gangrene and the like.

As another use of the present invention, there is one based onanti-oxidant action of HDL. The lipid peroxide concentration in blood isfar higher in HDL than in LDL, and HDL has a role of preventingperoxidation of lipid that occurs in living organisms, such as oxidationof LDL and the like (Current Opinion in Lipidology 4: 392-400, CurrentOpinion in Lipidology 5: 354-364).

As yet another use of the present invention, there is hypertension anddeuteropathy thereof. Hyperlipidemia aggravates arteriosclerosis andinduces hypertension. In contrast, HDL is known to prevent biosynthesisand to inhibit release of EDRF (epithelium-derived relaxing factor) byoxidized LDL, and increase prostacyclin, which is a vascular relaxingfactor, in macrophages (Current Opinion in Lipidology 5: 354-364). Inview of the lipid-lowering action and blood HDL-cholesterol increasingaction of the substance of the present invention, it is suitable for theprophylaxis or treatment of hypertension and deuteropathy thereof, suchas coronary heart disease (CHD), cerebral ischemia and the like. Forthis end, the compound of the formula (I) or (I′) or a salt thereof isused alone or in combination with a pharmaceutical agent exemplifiedbelow and can be administered. The possible combinations in this caseare, for example, angiotensin-II antagonists [e.g., losartan potassium(nu-lotan), dandesartan cilexetil (blopress) and the like], ACEinhibitors [e.g., enalapril maleate (renivase), lisinopril (zestril,longes), delapril hydrochloride (adecut), captopril and the like],calcium antagonists [e.g., amlodipine tosilate (amlodin, norvasc),manidipine hydrochloride (calslot) and the like], hypotensive diuretic,α receptor blocker, β receptor blocker and the like can be mentioned.

Some of the possible use of Compound (I) and Compound (I′) of thepresent invention is based on the cell protective action from cytotoxicsecretions such as gastric juice, pancreatic juice, bile and the like.Body fluid-tissue interfacial cells mainly expresses apo J, and form anatural barrier against cytotoxic secretions such as gastric juice,pancreatic juice, bile and the like, and HDL is a carrier of apo J(clusterin) (Current Opinion in Lipidology 4: 392-400). In considerationof the blood HDL-cholesterol increasing action of Compound (I) andCompound (I′) of the present invention, Compound (I) and Compound (I′)of the present invention are suitable for the prophylaxis or treatmentof gastric ulcer, pancreatitis, hepatitis and the like.

Some of still other possible use of Compound (I) and Compound (I′) ofthe present invention are based on cell growth activity. HDL alone ortogether with growth factor promotes cell growth of vascular endothelialcells (EC), corneal endothelium and the like, and HDL promotes growth ofhuman lymphocytes (Current Opinion in Lipidology 3: 222-226). Compound(I) and Compound (I′) of the present invention have a bloodHDL-cholesterol increasing action. In consideration of these cell growthactivities, they are suitable for the prophylaxis or treatment ofatherosclerotic vascular lesion and deuteropathy thereof, such ascoronary disease, corneal injury and the like. In addition, they arealso suitable for the prophylaxis or treatment of diseases based onlowered immunity, such as infectious diseases, malignant tumor and thelike.

As an additional use of Compound (I) and Compound (I′) of the presentinvention, HDL specifically acts on human placental transplanted tissueto cause secretion of lactogen, as well as promotes secretion of apoEfrom macrophages (Current Opinion in Lipidology 3: 222-226). Inconsideration of the secretion promoting activity, they are alsosuitable for the prophylaxis or treatment of fetal underdevelopment andthe like.

As a more noteworthy application example of Compound (I) and Compound(I′), secondary hyperlipidemia can be mentioned. This includes diabetes,insulin resistance (syndrome X), hypothyroidism, nephrotic syndrome,chronic kidney failure and the like, and these diseases cause onset ofhyperlipidemia. In most cases, it is said that hyperlipidemia aggravatesthese diseases, thereby forming what is called a vicious circle. In viewof the lipid lowering action, Compound (I) and Compound (I′) are alsosuitable for the treatment of these diseases and prevention ofprogression thereof. For this end, Compound (I) and Compound (I′) areused alone or in combination with a known active compound, i.e., forcombined use with therapeutic drugs of diabetes, for example, (1)diuretic (e.g., forosemide, spironolactone etc.), (2) sympatheticsuppressant (e.g., atenolol etc.), (3) angiotensin II antagonists (e.g.,losartan, candesartan etc.), (4) angiotensin I-converting enzymeinhibitors (e.g., enalapril maleate, delapril hydrochloride etc.), (5)calcium antagonists (e.g., nifedipine, manidipine hydrochloride etc.)and the like, for combined use with a therapeutic drug ofhypothyroidism, dry thyroid, levothyroxine sodium, liothyronine sodiumand the like, for combined use with a therapeutic drug of renal disease,prednisolone, sodium methylprednisolone succinate, furosemide,bumetanide, azosemide and the like, preferably by oral administration.

Compound (I) and Compound (I′) are also useful for the prophylaxis ortreatment of Alzheimer's disease. Increase in blood cholesterol is knownto a risk factor of Alzheimer's disease. The CETP inhibitors such as acompound represented by the formula (I) or (I′), a salt thereof, aprodrug thereof and the like can be used for the prophylaxis ortreatment of Alzheimer's disease, based on its superior HDL-cholesterolincreasing and lipid lowering action thereof. For this end, CETPinhibitors can be administered alone or in combination withpharmaceutical agents exemplified in the following. The possiblecombination in this case includes, for example, acetylcholine esteraseinhibitors (e.g., aricept, exelon and the like), amyloid β production.secretion inhibitors (e.g., γ or β selectase inhibitors such as JT-52,LY-374973 and the like, SIB-1848 and the like), amyloid β coagulationinhibitors (e.g., PTI-00703, BETABLOC (AN-1792) and the like) and thelike.

A still noteworthy applicable disease for Compound (I) and Compound (I′)is osteoporosis associated with increase in blood cholesterol. Becauseof the superior lipid-lowering action of Compound (I) and Compound (I′),the Compounds can be used for the prophylaxis or treatment ofosteoporosis associated with increase in blood cholesterol. For thisend, Compound (I) and Compound (I′) can be administered alone or incombination with pharmaceutical agents exemplified in the following. Thepossible combination in this case includes, for example, sex hormone andrelated pharmaceutical agents [e.g., estrogen preparation, ipriflavone(osten), raloxifene, osateron, tibolone and the like], calcitonins,vitamin D preparations [e.g., alfa calcidol, carcitriol and the like],bone resorption inhibitors such as bisphosphonic acids (e.g.,etidronate, clodronate etc.) and the like, osteogenesis promoters suchas fluorine compounds, PTH and the like, and the like.

In addition, Compound (I) and Compound (I′) are suitable for thetreatment of the diseases relating to hyperchylomicronemia such as acutepancreatitis. As the onset mechanism of pancreatitis, it is said thatchylomicron produces fine thrombus in pancreatic capillary, ortriglyceride is decomposed by pancreatic lipase due tohyperchylomicronemia and the resulting free fatty acid increases tocause strong focal irritation. Since Compound (I) and Compound (I′) ofthe present invention has a triglyceride-lowering action, they can treatpancreatitis, wherein they can be used alone or in combination withknown treatment method for the treatment of pancreatitis. For thetreatment of this disease, Compound (I) and Compound (I′) of the presentinvention can be administered orally or topically, wherein they can beused alone or in combination with known active compounds. The componentsthat can be combined in this case include, for example, aprotinin(trasylol), gabexate mesylate (FOY), nafamostat mesylate (futhan),citicoline (nicholin), urinastatin (miraclid) and the like forantienzymatic therapy. In addition, for removal of pain, anticholinergicdrug, non-narcotic analgesic, narcotic are also used.

A yet still possible use of Compound (I) and Compound (I′) of thepresent invention is inhibition of thrombus formation. Bloodtriglyceride level and factor VII involved in blood coagulation are inpositive correlation, wherein intake of ω-3 fatty acid lowerstriglyceride level as well as inhibits coagulation. Therefore,hypertriglyceridemia promotes formation of thrombus. In addition, sinceVLDL of hyperlipidemia patients increased secretion of plasminogenactivator inhibitor from vascular endothelial cells more strongly thandid regular lipidemia patients, triglyceride is also considered todegrade fibrinolytic activity. Therefore, in view of thetriglyceride-lowering action, Compound (I) and Compound (I′) aresuitable for the prophylaxis or treatment of thrombus formation. Forthis end, they can be used alone or in combination with knowntherapeutic drugs mentioned below, preferably by oral administration.

-   prophylactic or therapeutic drug of thrombus formation: blood    coagulation inhibitors [e.g., heparin sodium, heparin calcium,    warfarin calcium (warfarin), Xa inhibitor], thrombolytic agents    [e.g., tPA, urokinase], anti-platelet drugs [e.g., aspirin,    sulfinpyrazone (anturan), dipyridamole (persantin), ticlopidine    (panaldine), cilostazol (pletal), GPIIb/IIIa antagonists (reopro)]-   coronary vasodilators: nifedipine, diltiazem, nicoradil, nitrous    acid agents;-   cardiac muscle protective drug: heart ATP-K opener, endothelin    antagonists, urotensin antagonists and the like.

When the compound of the present invention is applied to theabove-mentioned diseases, it can be used in combination with biologicalpreparations (e.g.: antibody, vaccine preparations and the like), and itis also possible to apply as a combination therapy by combining with agene therapy method and the like. As the antibody and vaccinepreparation, for example, vaccine preparations to angiotensin II,vaccine preparations to CETP, CETP antibody, TNF_(α) antibody andantibody to other cytokines, amyloid β vaccine preparations, diabetes 1vaccines (DIAPEP-277 of Peptor Corp. and the like) and the like, as wellas antibody or vaccine preparation to cytokine, renin-angiotensinenzymes and the products thereof, antibody or vaccine preparation toenzyme or protein involved in blood lipid metabolism, antibody orvaccine relating to enzyme and protein involved in bloodcoagulation-fibrinolytic system, antibody or vaccine preparation toprotein involved in sugar metabolism and insulin resistance and the likecan be mentioned. As the gene therapy method, for example, a therapymethod using gene relating to cytokine, rennin-angiotensin enzymes andproducts thereof, a therapy method using DNA decoys such as NFκB decoyand the like, a therapy method using antisense, a therapy method using agene relating to the enzyme and protein involved in blood lipidmetabolism (e.g., gene relating to metabolism, excretion and absorptionof cholesterol or triglyceride or HDL-cholesterol or blood phospholipidand the like), a therapy method using a gene relating to enzyme andprotein (e.g., growth-factors such as HGF, VEGF etc., and the like)involved in angiogenesis therapy targeting peripheral vascularobstruction and the like, a therapy method using a gene relating toprotein involved in sugar metabolism and insulin resistance, antisenseto cytokines such as TNF and the like and the like can be mentioned. Itis also possible to use concurrently with various regeneration methodsof organs such as heart regeneration, renal regeneration, pancreaticregeneration, revascularization and the like, and angiogenesis therapyutilizing transplantation of bone marrow cells (bone marrow mononuclearcells, bone marrow stem cells and the like).

The dose of the preparation of the present invention varies depending onthe administration route, symptoms, age and body weight of patients andthe like. For example, in the case of oral administration to adultpatients as a therapeutic agent of arteriosclerosis, it is 0.2-50mg/day, preferably 1.5-30 mg/day, as Compound (I) or Compound (I′),which is preferably administered once or in several portions. Theadministration route may be either oral or parenteral.

The dose of the sustained release preparation of the present inventionvaries depending on the administration route, symptoms, age and bodyweight of patients and the like, as well as sustained time of releaseand the like. However, the dose is not particularly limited as long asthe effective concentration of Compound (I) or Compound (I′), which isan active ingredient, can be maintained in the body. The administrationfrequency can be determined appropriately and is once per one day to 3days or once per 1 week to 3 months and the like.

The experimental results showing the pharmacological effect of Compound(I) and Compound (I′) of the present invention are described in thefollowing.

EXPERIMENTAL EXAMPLE 1 Assay of Cholesteryl Ester Transfer ProteinInhibitory Activity

1) Preparation of Very Low Density Lipoprotein (VLDL)—Low DensityLipoprotein (LDL)

Fresh rabbit serum was adjusted with KBr to the density of (1.063 g/ml),and the fractions (VLDL-LDL, density<1.063 g/ml) floated byultra-centrifugation operation (SW41—Ti, 40,000 rpm, 18 hrs., 4° C.,Beckman model L8-55) were collected, subjected to dialysis against 0.15M NaCl-10 mM Tris-HCl, pH 7.4 (TBS), sterilized by filtration through afilter and preserved at 4° C.

2) Preparation of BODIPY-CE Microemulsion (BOBIPY-CE-ME)

A solution of BODIPY-CE (0.6 mg) in chloroform was added to egg PC(phosphatidylcholine) (5 ng) and triolein (2 mg), and after dissolution,the lipid was air dried under a nitrogen gas reflux and the solvent wasremoved under high vacuum. To this lipid was added an apo HDL solution(7.5 ml) obtained by defatting human HDL (1.063<d<1.21) withchloroform-methanol (2:1, v/v), dissolving in 6 M urea-containing TBSand dialyzing against TBS, and the mixture was subjected to sonication(BRANSON SONIFIRE CELL DISRUPTOR 200, dial 6, 5 min×4) to giveBOBIPY-CE-ME. After centrifugation (CENTRIPREP 10), it was sterilized byfiltration through a filter and preserved at 4° C.

3) Standard Measurement System

The test compound (20% DMSO solution, 5 μl), TS (75 μl), acceptorlipoprotein (VLDL-LDL, 20 μl) and partially purified human CETP (25 μl)were mixed and incubated at 37° C. for 30 min. BODIPY-CE-ME (25 μl) wasadded (total 150 μl) and a transfer reaction was started. After reactionat 37° C. for 30 min., fluorescence intensity was measured at Ex. 490nm/Em. 530 nm. The CETP inhibitory activity (% inhibition) wascalculated by the following formula.${\%\quad{inhibition}} = {\left( {1 - \frac{\left( {{FU}_{{test}\quad 30} - {FU}_{{test}\quad 0}} \right)}{\left( {{FU}_{{test}\quad 30} - {FU}_{{control}\quad 0}} \right)}} \right) \times 100}$4) 50% Human Plasma-Containing Measurement System

The test compound (20% DMSO solution, 5 μl), human plasma (75 μl),acceptor lipoprotein (VLDL-LDL, 20 μl) and partially purified human CETP(25 μl) were mixed and incubated at 37° C. for 30 min. BODIPY-CE-ME (25μl) was added (total 150 μl) and a transfer reaction was started. Afterreaction at 37° C. for 60 min., fluorescence intensity was measured atEx. 490 nm/Em. 530 nm. The CETP inhibitory activity (% inhibition) wascalculated by the following formula.${\%\quad{inhibition}} = {\left( {1 - \frac{\left( {{FU}_{{test}\quad 60} - {FU}_{{test}\quad 0}} \right)}{\left( {{FU}_{{test}\quad 60} - {FU}_{{control}\quad 0}} \right)}} \right) \times 100}$

The IC₅₀ value was determined as a concentration showing 50% inhibitionby plotting the logarithm of the concentration of test compound and %inhibition.

The results are shown in Table 1.

TABLE 1 cholesteryl ester transfer protein inhibitory activitycholesteryl ester transfer protein inhibitory activity IC₅₀ (μM)Standard 50% human plasma- compound measurement containing (Example No.)system measurement system  29 0.12 —  30 0.3 2.5 122 0.015 0.49 1230.035 0.95 124 0.046 2.4 125 0.051 2.0 126 0.070 1.0 155 0.095 2.1 1770.091 — 210 0.088 1.4 216 0.040 0.70 217 0.0084 0.08 218 0.056 0.66 2200.030 1.4 222 0.079 — 271 0.17 1.4 274 0.052 3.1 226(+)-form 0.4 4.2227(+)-form 0.21 1.7 228(+)-form 0.030 0.99 229(+)-form 0.0086 0.24

As is clear from the above-mentioned results, the present compound has asuperior cholesteryl ester transfer protein inhibitory activity.

EXAMPLES

The present invention is explained in detail in the following byreferring to Examples and Reference Examples, which are mere examplesand do not limit the invention, and may be modified as long as they donot deviate from the scope of the invention.

¹H-NMR spectra are determined with tetramethylsilane as the internalstandard, using the Varian GEMINI 200 (200 MHz) spectrometer; all δvalues are shown in ppm. Unless otherwise specifically indicated, thenumeral value shown for mixed solvent is volume mixing ratio of eachsolvent. Unless otherwise specifically indicated, “%” means % by weight.Unless otherwise specifically indicated, moreover, the elution solventfor silica gel chromatography shows volume ratios. Room temperature(normal temperature) in the present specification means a temperature offrom about 20° C. to about 30° C.

Each symbol in Examples and Reference Examples shows the followingmeaning. s: singlet, d:doublet, t:triplet, q:quartet, br: broad, J:coupling constant, dd: double doublet, m: multiplet, Hz: hertz, CDCl₃:deuterated chloroform, DMSO-d₆: deuterated dimethyl sulfoxide, CD₃OD:deuterated methanol, %: wt %.

Example 1N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-1-naphthalenecarboxamide

1) N-[2-(4-fluorophenyl)-2-oxoethyl]formamide

To a solution of α-bromo-4-fluoroacetophenone (30.0 g, 0.138 mol) inN,N-dimethylformamide (200 ml) was added sodium azide (8.99 g, 0.136mol) under ice-cooling and the mixture was stirred under ice-cooling for30 min. After diluting the reaction solution with water, the solutionwas extracted with ethyl acetate. The extract was washed successivelywith water and saturated brine, dried over magnesium sulfate andconcentrated under reduced pressure. The residue was dissolved inmethanol (300 ml). 10% Pd/C (containing water by 50%, 3.0 g) and conc.hydrochloric acid (12.7 ml, 0.152 mol) were added and the mixture wasstirred under hydrogen stream for 21 hrs. The catalyst was filtered offand the reaction solution was concentrated under reduced pressure. Amixed solution of sodium formate (10.3 g, 0.152 mol), acetic anhydride(140 ml) and formic acid (70 ml) was added to the residue and themixture was stirred at room temperature for 1 hr. The reaction solutionwas concentrated under reduced pressure, diluted with water, andextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over magnesium sulfate and concentrated under reducedpressure. The residue was recrystallized from ethyl acetate-hexane togive the objective substance (20.21 g, 81%) as crystals.

¹H-NMR (CDCl₃, 200 MHz) δ 4.79 (2H, dd, J=0.6 Hz, 4.4 Hz), 6.73 (1H, brs), 7.14-7.30 (2H, m), 7.97-8.10 (2H, m), 8.35 (1H, s).

2)2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethylformamide

To a solution of a suspension (0.55 g, 0.0138 mol) of 60% sodium hydridein liquid paraffin in N,N-dimethylformamide (16 ml) was addedN-[2-(4-fluorophenyl)-2-oxoethyl]formamide (1.66 g, 9.17 mmol) underice-cooling and the mixture was stirred for 30 min. To the reactionsolution was added 4-(trifluoromethyl)benzyl bromide (1.70 ml, 0.011mol), and the mixture was stirred at room temperature for 2 hrs. Thereaction solution was extracted with ethyl acetate. The extract waswashed successively with water and saturated brine, dried over magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethylacetate/hexane=1/2-1/1) to give the objective substance (1.65 g, 53%) ascrystals.

mp 78-81° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 3.13 (1H, dd, J=5.4 Hz, 13.8Hz), 3.38 (1H, dd, J=6.6 Hz, 14.0 Hz), 5.87-5.96 (1H, m), 6.52 (1H, brd, J=7.8 Hz), 7.07-7.25 (4H, m), 7.48 (2H, d, J=8.0 Hz), 7.93-8.04 (2H,m), 8.25 (1H, s); IR (KBr) 3295, 1680, 1661 cm⁻¹; Anal. Calcd forC₁₇H₁₃F₄NO₂: C, 60.18; H, 3.86; N, 4.13. Found: C, 59.99; H, 3.87; N,4.05;

3)2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethylaminehydrochloride

To a solution of2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethylformamide(13.87 g, 40.9 mmol) in methanol (100 ml) was added conc. hydrochloricacid (3.8 ml, 45.0 mmol), and the mixture was heated under reflux for 2hrs. The reaction solution was concentrated under reduced pressure, andthe residue was washed with ethyl acetate to give the objectivesubstance.(13.63 g, 96%) as crystals.

¹H-NMR (DMSO-d₆, 200 MHz) δ 3.17-3.29 (2H, m), 5.48 (1H, t, J=6.6 Hz),7.27-7.44 (4H, m), 7.59 (2H, d, J=8.0 Hz), 8.04-8.15 (2H, m), 8.38 (2H,br s).

4)N-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-1-naphthalenecarboxamide

To a solution of 1-naphthoic acid (0.49 g, 2.84 mmol) inN,N-dimethylformamide (10 ml) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.74 g,3.87 mmol) and 1-hydroxybenzotriazole hydrate (0.59 g, 3.87 mmol) andthe mixture was stirred for 5 min.2-(4-Fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethylaminehydrochloride (0.9 g, 2.58 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene(0.42 ml, 2.84 mmol) were added and the mixture was stirred for 3 hrs.The reaction solution was extracted with ethyl acetate. The extract waswashed successively with water and saturated brine, dried over magnesiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane=1/4)to give the objective substance (0.92 g, 77%) as crystals.

mp 163-164° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 3.19 (1H, dd, J=6.2 Hz, 13.8Hz), 3.55 (1H, dd, J=6.2 Hz, 14.0 Hz), 6.16 (1H, dd, J=6.2 Hz, 13.8 Hz),6.88 (1H, d, J=8.0 Hz), 7.15-7.30 (4H, m), 7.39-7.59 (6H, m), 7.83-7.97(2H, m), 8.04-8.16 (3H, m); IR (KBr) 3289, 1686, 1640 cm⁻¹; Anal.Calcdfor C₂₇H₁₉F₄NO₂.0.2H₂O: C, 69.14; H, 4.17; N, 2.99. Found: C, 69.27; H,4.07; N, 2.85.

5)N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-1-naphthalenecarboxamide

To a solution ofN-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-1-naphthalenecarboxamide(500 mg, 1.08 mmol) in methanol (5 ml) was added sodium borohydride (20mg, 0.538 mmol) and the mixture was stirred under ice-cooling for 30min. The reaction solution was extracted with ethyl acetate. The extractwas washed successively with 1N aqueous hydrochloric acid solution andsaturated brine, dried over magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane=1/2) to give the objectivesubstance (480 mg, 96%, (1RS,2SR) form/(1RS,2RS) form=1/3) as crystals.

mp 159-181° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 2.86 (1H×1/4, dd, J=11.0 Hz,14.6 Hz), 3.07 (1H×3/4, dd, J=4.8 Hz, 15.0 Hz), 3.19 (1H, d, J=7.8 Hz),3.27 (1H×3/4, d, J=4.6 Hz), 3.37 (1H×1/4, d, J=3.6 Hz), 4.61 (1H×3/4,ddd, J=3.4 Hz, 7.6 Hz, 16.8 Hz), 4.73-4.86 (1H×1/4, m), 4.89 (1H×3/4, t,J=7.8 Hz), 5.08 (1H×1/4, t, J=3.6 Hz), 5.98 (1H×1/4, d, J=8.4 Hz), 6.20(1H×/4, d, J=9.2 Hz), 6.99-7.14 (2H, m), 7.16-7.55 (9H, m), 7.60 (2H, d,J=8.4 Hz), 7.83 (2H, t, J=8.8 Hz); IR (KBr) 3384, 3304, 1645 cm⁻¹; Anal.Calcd for C₂₇H₂₁F₄NO₂: C, 69.37; H, 4.53; N, 3.00. Found: C, 69.21; H,4.58; N, 3.03.

Example 2N-(2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-methyl-1-naphthalenecarboxamide

1) To a solution of1-(4-fluorophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (600 mg, 1.73 mmol) and 4-methyl-1-naphthalenecarboxylicacid (354 mg, 1.90 mmol) in N,N-dimethylformamide (10 ml) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (496 mg,2.59 mmol), 1-hydroxy-1H-benzotriazole (396 mg, 2.59 mmol) and1,8-diazabicyclo[5.4.0]-7-undecene (0.28 ml, 1.90 mmol) and the mixturewas stirred overnight. To the reaction solution were added 1N aqueoushydrochloric acid solution (10 ml) and water (100 ml), and the mixturewas extracted with ethyl acetate (50 ml×2): The extract was washed with1N aqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1 and recrystallized from ethyl acetate-hexane to giveN-(2-(4-fluorophenyl)-2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-methyl-1-naphthalenecarboxamide(665 mg, 80%).

mp 149-150° C. IR ν max^(KBr)cm⁻¹: 1693, 1634, 1539, 1510. Anal. Calcdfor C₂₈H₂₁F₄NO₂: C, 70.14; H, 4.41; N, 2.92. Found: C, 70.09; H, 4.42;N, 2.91.

¹H-NMR (CDCl₃)δ: 2.71 (3H, s), 3.19 (1H, dd, J=14.0, 6.2 Hz), 3.55 (1H,d, J=14.0, 6.2 Hz), 6.16 (1H, q, J=7.0 Hz), 6.83 (1H, d, J=7.4 Hz),7.14-7.32 (5H, m), 7.36-7.64 (5H, m), 7.98-8.18 (4H, m).

2) To a solution ofN-(2-(4-fluorophenyl)-2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-methyl-1-naphthalenecarboxamide(400 mg, 0.83 mmol) in methanol (30 ml) was added manganese (II)chloride (210 mg, 1.67 mmol), and the mixture was stirred at roomtemperature for 30 min. To the reaction solution were added sodiumborohydride (63 mg, 1.67 mmol) under ice-cooling, and the mixture wasstirred for 1 hr. The reaction solution was poured into 1N hydrochloricacid (30 ml) and extracted with ethyl acetate (50 ml×2). The extract waswashed with water and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=2:1), and theobtained crude crystal was washed with a mixed solvent of hexane:ethylacetate=10:1 to give the title compound ((1RS,2SR) form: (1RS,2RS)form=1:2, 329 mg, 82%).

IR ν max^(KBr)cm⁻¹: 1634, 1510, 1125. Anal. Calcd for C₂₈H₂₃F₄NO₂: C,69.85; H, 4.81; N, 2.91. Found: C, 69.56; H, 4.75; N, 2.80. ¹H-NMR(CDCl₃)δ: 2.66 (3H, s), 2.70-3.10 (1H, m), 3.44 (2/3H, d, J=4.8 Hz),3.53 (1/3H, d, J=3.6 Hz), 4.50-4.68 (2/3H, m), 4.70-4.90 (1H, m),5.04-5.10 (1/3H, m), 5.95 (1/3H, d, J=8.8 Hz), 6.19 (2/3H, d, J=8.8 Hz),6.96-7.70 (13H, m), 7.96 (1H, d, J=8.4 Hz).

Example 3N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-4-phenylbutylamide

1)N-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-4-phenylbutylamide

In the same manner as in Example 1 4), the objective substance (1.01 g,77%) was obtained as crystals.

mp 133-135° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 1.87-2.02 (2H, m), 2.18-2.26(2H, m), 2.62 (2H, t, J=7.4 Hz), 3.08 (1H, dd, J=5.2 Hz, 14.0 Hz), 3.33(1H, dd, J=6.6 Hz, 13.8 Hz), 5.78-5.88 (1H, m), 6.26 (1H, d, J=7.6 Hz),7.05-7.33 (9H, m), 7.45 (2H, d, J=8.2 Hz), 7.92-8.03 (2H, m); IR (KBr)3281, 1645 cm⁻¹; Anal. Calcd for C₂₆H₂₃F₄NO₂: C, 68.26; H, 5.07; N,3.06. Found: C, 68.07; H, 4.79; N, 3.10.

2)N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-4-phenylbutylamide

In the same manner as in Example 1 5), the objective substance (144 mg,29%, (1RS,2SR) form/(1RS,2RS) form=4/1) was obtained as crystals.

mp 145-151° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 1.70-1.90 (2H, m), 2.00-2.14(2H, m), 2.51 (2H, t, J=7.4 Hz), 2.70-2.94 (2H, m), 3.44 (1H, d, J=3.6Hz), 4.30-4.56 (1H, m), 4.92-5.00 (1H, m), 5.38 (1H, d, J=7.0 Hz),7.00-7.60 (13H, m); IR (KBr) 1645 cm⁻¹; Anal. Calcd for C₂₆H₂₅F₄NO₂: C,67.96; H, 5.48; N, 3.05. Found: C, 67.85; H, 5.61; N, 3.04.

Example 4N-(2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-(2-thienyl)butyramide

1) To a solution of1-(4-fluorophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (600 mg,1.73 mmol) and 4-(2-thienyl)butyric acid (323 mg,1.90 mmol) in N,N-dimethylformamide (10 ml) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (496 mg,2.59 mmol), 1-hydroxy-1H-benzotriazole (396 mg, 2.59 mmol) and1,8-diazabicyclo[5.4.0]-7-undecene (0.28 ml, 1.90 mmol) and the mixturewas stirred overnight. To the reaction solution were added 1N aqueoushydrochloric acid solution (10 ml) and water (100 ml), and the mixturewas extracted with ethyl acetate (50 ml×2). The extract was washed with1N aqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to giveN-(2-(4-fluorophenyl)-2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-(2-thienyl)butyramide(445 mg, 56%).

mp 123-124° C. IR ν max^(KBr)cm⁻¹: 3275, 1651, 1597, 1508, 1325, 1232,1159, 1124. Anal. Calcd for C₂₄H₂₁F₄NO₂S: C, 62.19; H, 4.57; N, 3.02.Found: C, 62.02; H, 4.69; N, 3.28. ¹H-NMR (CDCl₃)δ: 1.94-2.10 (2H, m),2.26 (2H, t, J=7.4 Hz), 2.84 (2H, t, J=7.4 Hz), 3.08 (1H, dd, J=14.0,5.2 Hz), 3.33 (1H, d, J=14.0, 5.2 Hz), 5.84 (1H, q, J=-6.4 Hz), 6.28(1H, d, J=7.4 Hz), 6.74-6.80 (1H, m), 6.86-6.96 (1H, m), 7.04-7.24 (5H,m), 7.46 (2H, d, J=8.0 Hz), 7.92-8.06 (2H, m).

2) To a solution ofN-(2-(4-fluorophenyl)-2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-(2-thienyl)butyramide(300 mg, 0.65 mmol) in methanol (30 ml) was added manganese (II)chloride (163 mg, 1.30 mmol), and the mixture was stirred at roomtemperature for 30 min. To the reaction solution was added sodiumborohydride (49 mg, 1.30 mmol) under ice-cooling, and the mixture wasstirred for 1 hr. The reaction solution was poured into 1N hydrochloricacid (30 ml) and extracted with ethyl acetate (50 ml×2). The extract waswashed with water and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=2:1), and theobtained crude crystal was washed with a mixed solvent of hexane:ethylacetate=10:1 to give the title compound ((1RS,2SR) form: (1RS,2RS)form=1:1, 204 mg, 68%).

IR ν max^(KBr)cm⁻¹: 1645, 1510, 1225, 1165, 1125. Anal. Calcd forC₂₄H₂₃F₄NO₂S: C, 61.92; H, 4.98; N, 3.01. Found: C, 61.94; H, 4.98; N,2.94. ¹H-NMR (CDCl₃)δ: 1.70-1.96 (2H, m), 2.00-2.16 (2H, m), 2.60-3.00(3H, m), 3.43 (1/2H, d, J=5.2 Hz), 3.51 (1/2H, d, J=3.6 Hz), 4.14-4.32(1/2H, m), 4.36-4.52 (1/2H, m), 4.68-4.80 (1/2H, m), 4.90-4.98 (1/2H,m), 5.44 (1/2H, d, J=8.4 Hz), 5.66 (1/2H, d, J=8.4 Hz), 6.62-6.72 (1H,m), 6.88-7.60 (10H, m).

Example 5N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]cyclopentanecarboxamide

1) 1)N-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]cyclopentanecarboxamide

In the same manner as in Example 1 4), the objective substance, (0.84 g,71%) was obtained as crystals.

mp 158-159° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 1.64-1.93 (8H, m), 2.47-2.64(1H, m), 3.08 (1H, dd, J=5.6 Hz, 13.6 Hz), 3.35 (1H, dd, J=6.6 Hz, 13.8Hz), 5.78-5.88 (1H, m), 6.30 (1H, br d, J=7.2 Hz), 7.09 (2H, d, J=8.0Hz), 7.12-7.23 (2H, m), 7.47 (2H, d, J=8.0 Hz), 7.94-8.02 (2H, m); IR(KBr) 3274, 1684, 1644 cm⁻¹; Anal. Calcd for C₂₂H₂₁F₄NO₂: C, 64.86; H,5.20; N, 3.44. Found: C, 64.77; H, 5.13; N, 3.36.

2)N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]cyclopentanecarboxamide

In the same manner as in Example 1 5), the objective substance (433 mg,86%, (1RS,2SR) form/(1RS,2RS) form=3/4) was obtained as crystals.

mp 139-155° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 1.40-1.80 (8H, m), 2.36 (1H,br s), 2.71-3.07 (2H, m), 3.73-3.78 (1H, m), 4.12 (1H×4/7, ddd, J=3.6Hz, 8.0. Hz, 15.4 Hz), 4.33-4.47 (1H×3/7, m), 4.75 (1H×4/7, t, J=7.2Hz), 4.95 (1H×3/7, t, J=6.6 Hz), 5.40 (1H×3/7, br d, J=8.4 Hz), 5.62(1H, br d, J=8.0 Hz), 6.94-7.14 (2H, m), 7.17-7.30 (2H, m), 7.32-7.42(2H, m), 7.47-7.60 (2H, m); IR (KBr) 3312, 1651 cm⁻¹; Anal. Calcd forC₂₂H₂₃F₄NO₂: C, 64.54; H, 5.66; N, 3.42. Found: C, 64.58; H, 5.89; N,3.67.

Example 64-fluoro-N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzamide

1)4-fluoro-N-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzamide

In the same manner as in Example 1 4), the objective substance (1.16 g,93%) was obtained as crystals.

mp 171-172° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 3.22 (1H, dd, J=5.0 Hz, 13.8Hz), 3.49 (1H, dd, J=6.6 Hz, 14.0 Hz), 6.00 (1H, m), 6.97-7.28 (7H, m),7.46 (2H, d, J=8.0 Hz), 7.74-7.85 (2H, m), 7.97-8.09 (2H, m); IR (KBr)3316, 1698, 1638 cm⁻¹; Anal. Calcd for C₂₃H₁₆F₅NO₂: C, 63.74; H, 3.72;N, 3.23. Found: C, 63.57; H, 3.87; N, 3.23.

2)4-fluoro-N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzamide

In the same manner as in Example 1 5), the objective substance (423 mg,94%, (1RS,2SR) form/(1RS,2RS) form=3/7) was obtained as crystals.

mp 155-179° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 2.90-2.97 (2H×1/3, m), 3.14(2H×2/3, d, J=7.6 Hz), 3.22 (1H×2/3, d, J=4.2 Hz), 3.48 (1H×1/3, d,J=3.8 Hz), 4.42 (1H×2/3, ddd, J=3.4 Hz, 7.2 Hz, 15.8 Hz), 4.51-4.68(1H×1/3, m), 4.83 (1H×2/3, t, J=3.9 Hz), 5.08 (1H×1/3, t, J=3.1 Hz),6.09 (1H×1/3, br d, J=8.4 Hz), 6.34 (1H×2/3, br d, J=8.4 Hz), 6.93-7.13(4H, m), 7.20-7.32 (2H, m), 7.37-7.62 (6H, m); IR (KBr) 3301, 1636 cm⁻¹;Anal. Calcd for C₂₃H₁₈F₅NO₂: C, 63.45; H, 4.17; N, 3.22. Found: C,63.34; H, 4.36; N, 3.24.

Example 7N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-4-methoxybenzamide

1)N-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-4-methoxybenzamide

In the same manner as in Example 1 4), the objective substance (1.11 g,87%) was obtained as crystals.

mp 144° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 3.21 (1H, dd, J=4.8 Hz, 14.0 Hz),3.48 (1H, dd, J=6.6 Hz, 13.6 Hz), 3.86 (3H, s), 6.01 (1H, ddd, J=4.6 Hz,4.8 Hz, 6.6 Hz), 6.90-7.02 (3H, m), 7.08 (2H, d, J=8.2 Hz), 7.12-7.25(2H, m), 7.45 (2H, d, J=8.0 Hz), 7.71-7.79 (2H, m), 7.97-8.08 (2H, m);IR (KBr) 3279,1694, 1651 cm⁻¹; Anal. Calcd for C₂₄H₁₉F₄NO₃: C, 64.72; H,4.30; N, 3.14. Found: C, 64.53; H, 4.27; N; 3.25.

2)N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-4-methoxybenzamide

In the same manner as in Example 1 5), the objective substance (0.48 g,96%, (1RS,2SR) form/(1RS,2RS) form=3/2) was obtained as crystals.

mp 174-176° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 2.90-2.98 (2H×3/5, m), 3.12(2H×2/5, d, J=7.4 Hz), 3.76 (1H×2/5, d, J=4.8 Hz), 3.82 (3H, s), 3.99(1H×3/5, d, J=3.6 Hz), 4.28-4.46 (1H×2/5, m), 4:49-4.66; (1H×3/5, m),4.81 (1H×2/5, t, J=8.2 Hz), 5.06 (1H×3/5, t, J=3.0 Hz), 6.08 (1H×3/5, d,J=8.2 Hz), 6.32 (1H×2/5, d, J=8.6 Hz), 6.82-7.13 (4H, m), 7.20-7.32 (2H,m), 7.34-7.59 (6H, m); IR (KBr) 3341, 1609 cm⁻¹; Anal. Calcd forC₂₄H₂₁F₄NO₃: C, 64.43; H, 4.73; N, 3.13. Found: C, 64.49; H, 4.74; N,3.02.

Example 8N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]cyclohexanecarboxamide

1)N-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]cyclohexanecarboxamide

In the same manner as in Example 1 4), the objective substance (0.90 g,83%) was obtained as crystals.

mp 169-170° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 1.51-1.52 (5H, m), 1.62-1.88(5H, m), 2.04-2.20 (1H, m), 3.08 (1H, dd, J=4.8 Hz, 14.0 Hz), 3.35 (1H,dd, J=6.2 Hz, 13.8 Hz), 5.76-5.88 (1H, m), 6.30 (1H, d, J=7.6 Hz), 7.07(2H, d, J=8.2 Hz), 7.17 (2H, t, J=17.2 Hz), 7.47 (2H, d, J=8.0 Hz),7.93-8.04 (2H, m); IR (KBr) 3274, 1686, 1640 cm⁻¹; Anal. Calcd forC₂₃H₂₃F₄NO₂: C, 65.55; H, 5.50; N, 3.32. Found: C, 65.52; H, 5.48; N,3.44.

2)N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]cyclohexanecarboxamide

In the same manner as in Example 1 5), the objective substance (480 mg,96%, (1RS,2SR) form/(1RS,2RS) form=1/1) was obtained as crystals.

mp 161-178° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 1.08-1.34 (5H, m), 1.48-1.80(5H, m), 1.92 (1H, br s), 2.77 (0.5H, dd, J=9.8 Hz, 14.6 Hz), 2.90(0.5H, dd, J=5.4 Hz, 14.6 Hz), 3.06 (1H, d, J=7.8 Hz), 3.76 (0.5H, d,J=2.0 Hz), 3.79 (0.5H, s), 4.11 (0.5H, ddd, 3.8 Hz, 7.8 Hz, 15.8 Hz),4.33-4.50 (0.5H, m), 4.76 (0.5H, t, J=9.0 Hz), 4.94 (0.5H, t, J=7.0 Hz),5.38 (0.5H, d, J=8.2 Hz), 5.61 (0.5H, d, J=8.4 Hz), 6.95-7.12 (2H, m),7.18-7.29 (2H, m), 7.32-7.41 (2H, m), 7.5.4 (2H, t, J=18.0 Hz); IR (KBr)3384, 3304, 1645 cm⁻¹; Anal. Calcd for C₂₃H₂₅F₄NO₂: C, 65.24; H, 5.95;N, 3.31. Found: C, 64.99; H, 5.97; N, 3.25.

Example 94-chloro-N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzamide

1)4-chloro-N-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzamide

In the same manner as in Example 1 4), the objective substance (1.20 g,92%) was obtained as crystals.

mp 150-153° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 3.22 (1H, dd, J=4.8 Hz, 14.0Hz), 3.49 (1H, dd, J=6.2 Hz, 14.0 Hz), 6.00 (1H, ddd, J=4.8 Hz, 6.6 Hz,6.6 Hz), 7.02 (1H, br s), 7.07 (2H, d, J=7.6 Hz), 7.20 (2H, t, J=8.6Hz), 7.44 (2H, d, J=8.4 Hz), 7.46 (2H, d, J=8.0 Hz), 7.72 (2H, d, J=8.8Hz), 7.97-8.08 (2H, m); IR (KBr) 3281, 1686, 1644 cm⁻¹; Anal. Calcd forC₂₃H₁₆ClF₄NO₂: C, 61.41; H, 3.59; N, 3.11. Found: C, 61.41; H, 3.80; N,3.09.

2)4-chloro-N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzamide

In the same manner as in Example 1 5), the objective substance (467 mg,93%, (1RS,2SR) form/(1RS,2RS) form=1/1) was obtained as crystals.

mp 170-180° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 2.92 (0.5H, br s), 2.96 (0.5H,s), 3.04 (0.5H, d, J=4.8 Hz), 3.15 (1H, d, J=7.8 Hz), 3.32 (0.5H, d,J=3.8 Hz), 4.35-4.50 (0.5H, m), 4.53-4.68 (0.5H, m), 4.84 (0.5H, T,J=3.7 Hz), 5.08 (0.5H, t, J=3.8 Hz), 6.08 (0.5H, br d, J=7.4 Hz), 6.34(0.5H, br d, J=9.2 Hz), 6.94-7.14 (2H, m), 7.21-7.61 (10H, m); IR (KBr)3310, 1645 cm⁻¹; Anal. Calcd for C₂₃H₁₈ClF₄NO₂: C, 61.14; H, 4.02; N,3.10. Found: C, 61.10; H, 4.22; N, 3.15.

Example 10N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-2-phenylbenzamide

1)N-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-2-phenylbenzamide

In the same manner as in Example 1 4), the objective substance (0.81 g,57%) was obtained as crystals.

mp 148-149° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 2.93 (1H, dd, J=5.2 Hz, 13.6Hz), 3.06 (1H, dd, J=6.6 Hz, 14.0 Hz), 5.80 (1H, ddd, J=5.6 Hz, 6.6 Hz,9.2 Hz), 6.19 (1H, d, J=7.6 Hz), 6.89 (2H, d, J=8.4 Hz), 7.11 (2H, t,J=8.4 Hz), 7.27-7.62 (1H, m), 7.87 (2H, dd, J=5.0 Hz, 8.6 Hz); IR (KBr)3281, 1684 cm⁻¹; Anal. Calcd for C₂₉H₂₁F₄NO₂: C, 70.87; H, 4.31; N,2.85. Found: C, 70.87; H, 4.30; N, 2.83.

2)N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-2-phenylbenzamide

In the same manner as in Example 1 5), the objective substance (0.48 g,95%, (1RS,2SR) form/(1RS,2RS) form=2/3) was obtained as crystals.

mp 133-134° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 2.25-2.88 (3H, m), 4.22-4.52(1H, m), 4.54 (1H×3/5, t, J=4.4 Hz), 4.64 (1H×2/5, t, J=3.8 Hz), 5.39(1H×2/5, d, J=8.8 Hz), 5.65 (1H×3/5, d, J=8.2 Hz), 6.92-7.15 (4H, m),7.20-7.56 (13H, m); IR (KBr) 3335, 1645 cm⁻¹; Anal. Calcd forC₂₉H₂₃F₄NO₂: C, 70.58; H, 4.70; N, 2.84. Found: C, 70.46; H, 4.62; N,2.93.

Example 11N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-2-thiophenecarboxamide

1)N-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-2-thiophenecarboxamide

In the same manner as in Example 1 4), the objective substance (0.94 g,78%) was obtained as crystals.

mp 130-131° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 3.21 (1H, dd, J=4.8 Hz, 13.8Hz), 3.46 (1H, dd, J=6.4 Hz, 13.6 Hz), 5.93-6.04 (1H, m), 6.91 (1H, d,J=7.0 Hz), 7.05-7.24 (5H, m), 7.45 (2H, d, J=8.2 Hz), 7.50-7.54 (2H, m),7.96-8.06 (2H, m); IR (KBr) 3308, 1694, 1682 cm⁻¹; Anal. Calcd forC₂₁H₁₅F₄NO₂S: C, 59.85; H, 3.59; N, 3.32. Found: C, 59.83; H, 3.34; N,3.24.

2)N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-2-thiophenecarboxamide

In the same manner as in Example 1 5), the objective substance (0.45 g,89%, (1RS,2SR) form/(1RS,2RS) form=2/1) was obtained as crystals.

mp 135-164° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 2.92 (2H×2/3, d, J=7.8 Hz),3.10-3.15 (1H, m), 3.40 (1H×2/3, d, J=3.8 Hz), 4.30-4.64 (1H, m), 4.82(1H×1/3, t, J=4.0 Hz), 5.08 (1H×2/3, t, J=3.3 Hz), 6.00 (1H×2/3, br d,J=8.4 Hz), 6.25 (1H×1/3, br d, J=8.4 Hz), 6.94-7.14 (3H, m), 7.21-7.61(8H, m); IR (KBr) 3301, 1636 cm⁻¹; Anal. Calcd for C₂₁H₁₇F₄NO₂S: C,59.57; H, 4.05; N, 3.31. Found: C, 59.59; H, 4.15; N, 3.24.

Example 12N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-4-(trifluoromethyl)benzamide

1)N-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-4-(trifluoromethyl)benzamide

In the same manner as in Example 1 4), the objective substance (1.32 g,95%) was obtained as crystals.

mp 172-174° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 3.23 (1H, dd, J=4.8 Hz, 13.8Hz), 3.51 (1H, dd, J=6.2 Hz, 14.0 Hz), 6.01 (1H, ddd, J=5.2 Hz, 6.4 Hz,7.0 Hz), 7.08 (2H, d, J=8.0 Hz), 7.14 (1H, br s), 7.21 (2H, t, J=8.6Hz), 7.47 (2H, d, J=8.0 Hz), 7.73 (2H, d, J=8.4 Hz), 7.88 (2H, d, J=8.4Hz), 7.98-8.10 (2H, m); IR (KBr) 3303, 1688, 1645 cm⁻¹; Anal. Calcd forC₂₄H₁₆F₇NO₂: C, 59.63; H, 3.34; N, 2.90. Found: C, 59.55; H, 3.58; N,2.89.

2)N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-4-(trifluoromethyl)benzamide

In the same manner as in Example 1 5), the objective substance (444 mg,88%, (1RS,2SR) form/(1RS,2RS) form=1/6) was obtained as crystals.

mp 167-169° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 2.87 (1H, d, J=4.4 Hz), 3.17(2H, d, J=7.6 Hz), 4.40-4.56 (1H, m), 4.86 (1H×6/7, t, J=3.4 Hz), 5.10(1H×1/7, s), 6.43 (1H, d, J=8.8 Hz), 6.95-7.14 (2H, m), 7.22-7.32 (2H,m), 7.43 (2H, d, J=8.2 Hz), 7.59 (2H, d, J=8.4 Hz), 7.67 (4H, s); IR(KBr) 3426, 3335, 1645 cm⁻¹; Anal. Calcd for C₂₄H₁₈F₇NO₂: C, 59.39; H,3.74; N, 2.89. Found: C, 59.34; H, 3.961; N, 2.89.

Example 134-butyl-N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzamide

1)4-butyl-N-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzamide

In the same manner as in Example 1 4), the objective substance (1.16 g,86%) was obtained as crystals.

mp 120-121° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 0.93 (3H, t, J=7.1 Hz),1.26-1.46 (2H, m), 1.53-1.70 (2H, m), 2.67 (2H, t, J=7.6 Hz), 3.21 (1H,dd, J=4.6 Hz, 13.8 Hz), 3.49 (1H, dd, J=6.4 Hz, 13.6 Hz), 6.02 (1H, ddd,J=4.8 Hz, 6.4 Hz, 7.4 Hz), 7.00-7.28 (7H, m), 7.45 (2H, d, J=8.2 Hz),7.69 (2H, d, J=8.2 Hz), 7.97-8.08 (2H, m); IR (KBr) 3281, 1688, 1636cm⁻¹; Anal. Calcd for C₂₇H₂₅F₄NO₂: C, 68.78; H, 5.34; N, 2.97. Found: C,68.95; H, 5.43; N, 2.96.

2)4-butyl-N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzamide

In the same manner as in Example 1 5), the objective substance (946 mg,95%, (1RS,2SR) form/(1RS,2RS) form=4/3) was obtained as crystals.

mp 138-158° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 0.92 (3H, t, J=7.1 Hz),1.24-1.43 (2H, m), 1.50-1.67 (2H, m), 2.63 (2H, t, J=7.7 Hz), 2.90(1H×4/7,d, J=3.4 Hz), 2.94 (1H×4/7, s), 3.13 (2H×3/7, d, J=4.4 Hz), 3.88(1H×4/7, d, J=3.8 Hz), 4.37 (1H×3/7, ddd, J=2.8 Hz, 7.0 Hz, 15.4 Hz),4.52-4.67 (1H×4/7, m), 4.82 (1H×3/7, t, J=4.2 Hz), 5.06 (1H×4/7, t,J=3.5 Hz), 6.14 (1H×4/7, d, J=8.2 Hz), 6.37 (1H×3/7, d, J=8.6 Hz),6.91-7.32 (6H, m), 7.35-7.59 (6H, m); IR (KBr) 3274, 1615 cm⁻¹; Anal.Calcd for C₂₇H₂₇F₄NO₂: C, 68.49; H, 5.75; N, 2.96. Found: C, 68.35; H,5.89; N, 3.04.

Example 14N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-2-naphthalenecarboxamide

1)N-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-2-naphthalenecarboxamide

In the same manner as in Example 1 4), the objective substance (1.03 g,77%) was obtained as crystals.

mp 139-141° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 3.26 (1H, dd, J=4.8 Hz, 14.0Hz), 3.54 (1H, dd, J=6.6 Hz, 13.4 Hz), 6.04-6.14 (1H, m), 7.11 (2H, d,J=8.2 Hz), 7.17-7.28 (3H, m), 7.46 (2H, d, J=8.0 Hz), 7.51-7.64 (2H, m),7.80-7.97 (4H, m), 8.01-8.11 (2H, m), 8.29 (1H, s); IR (KBr) 3293, 1694,1645 cm⁻¹; Anal. Calcd for C₂₇H₁₉F₄NO₂: C, 69.67; H, 4.11; N, 3.01.Found: C, 69.67; H, 4.11; N, 3.01.

2)N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-2-naphthalenecarboxamide

In the same manner as in Example 1 5), the objective substance (0.50 g,100%, (1RS,2SR) form/(1RS,2RS) form=1/1) was obtained as crystals.

mp 148-150° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 3.00 (1H, d, J=7.8 Hz), 3.20(1H, d, J=7.8 Hz), 3.38-3.53 (0.5H, m), 3.67-3.77 (0.5H, m), 4.39-4.55(0.5H, m), 4.59-4.75 (0.5H, m), 4.85-4.93 (0.5H, m), 5.14 (0.5H, t,J=3.0 Hz), 6.28 (0.5H, br s), 6.53 (0.5H, br s), 6.94-7.13 (2H, m),7.26-7.36 (2H, m), 7.41-7.65 (7H, m), 7.82-7.89 (3H, m), 8.04 (1H, d,J=4.4 Hz); IR (KBr) 3351, 1640 cm⁻¹; Anal. Calcd for C₂₇H₂₁F₄NO₂: C,69.37; H, 4.53; N, 3.00. Found: C, 68.51; H, 5.02; N, 2.67.

Example 15N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]adamantane-1-carboxamide

1)N-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]adamantane-1-carboxamide

In the same manner as in Example 1 4), the objective substance (0.89 g,78%) was obtained as crystals.

mp 169-170° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 1.71 (6H, d, J=2.6 Hz), 1.81(6H, d, J=3.0 Hz), 2.04 (3H, br s), 3.08 (1H, dd, J=5.2 Hz, 13.6 Hz),3.34 (1H, dd, J=6.6 Hz, 14.0 Hz), 5.75-5.85 (1H, m), 6.49 (1H, br d,J=7.6 Hz), 7.07 (1H, d, J=7.8 Hz), 7.11-7.23 (2H, m), 7.47 (2H, d, J=8.0Hz), 7.93-8.03 (2H, m); IR (KBr) 3347, 1682, 1632 cm⁻¹; Anal. Calcd forC₂₇H₂₇F₄NO₂: C, 68.49; H, 5.75; N, 2.96. Found: C, 68.41; H, 5.70; N,2.93.

2)N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]adamantane-1-carboxamide

In the same manner as in Example 1 5), the objective substance (488 mg,97%, (1RS,2SR) form/(1RS,2RS) form=3/2) was obtained as an amorphouscompound.

¹H-NMR (CDCl₃, 200 MHz) δ 1.55-1.74 (12H, m), 1.97 (3H, br s), 2.63-3.06(2H, m), 4.01 (1H, br t, J=3.4 Hz), 4.09 (1H×2/5, ddd, J=4.0 Hz, 7.6 Hz,15.6 Hz), 4.33-4.47 (1H×3/5, m), 4.75 (1H×2/5, t, J=8.8 Hz), 4.91(1H×3/5, t, J=6.6 Hz), 5.48 (1H×3/5, d, J=7.6 Hz), 5.76 (1H×2/5, d,J=8.0 Hz), 6.94-7.13 (2H, m), 7.17-7.28 (2H, m), 7.30-7.40 (2H, m),7.48-7.59 (2H, m); IR (KBr) 3441, 3353, 1634 cm⁻¹; Anal. Calcd forC₂₇H₂₉F₄NO₂: C, 68.20; H, 6.15; N, 2.95. Found: C, 67.72; H, 6.31; N,2.86.

Example 16N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-2,2-dimethylpropionamide

1)N-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-2,2-dimethylpropionamide

In the same manner as in Example 1 4), the objective substance (0.89 g,78%) was obtained as crystals.

mp 147-150° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 1.17 (9H, s), 3.08 (1H, dd,J=5.2 Hz, 13.6 Hz), 3.35 (1H, dd, J=6.2 Hz, 14.0 Hz), 5.74-5.84 (1H, m),6.52 (1H, br d, J=6.6 Hz), 7.08 (2H, d, J=7.6 Hz), 7.12-7.24 (2H, m),7.47 (2H, d, J=8.0 Hz), 7.94-8.04 (2H, m); IR (KBr) 3391, 1682, 1634cm⁻¹; Anal. Calcd for C₂₁H₂₁F₄NO₂: C, 63.79; H, 5.35; N, 3.54. Found: C,63.72; H, 5.21; N, 3.48.

2)N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-2,2-dimethylpropionamide

In the same manner as in Example 1 5), the objective substance (498 mg,99%, (1RS,2SR) form/(1RS,2RS) form=3/2) was obtained as crystals.

mp 97-99° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 1.00 (9H, s), 2.69-3.08 (2H, m),3.83 (1H, br s), 4.13 (1H×2/5, ddd, J=3.6 Hz, 8.0 Hz, 15.8 Hz),4.34-4.47 (1H×3/5, m), 4.76 (1H×2/5, t, J=4.0 Hz), 4.92 (1H×3/5, t,J=3.2 Hz), 5.54 (1H×3/5, t, J=7.0 Hz), 5.83 (1H×2/5, m), 6.95-7.12 (2H,m), 7.17-7.25 (2H, m), 7.31-7.40 (2H, m), 7.47-7.59 (2H, m); IR (KBr)3333, 1645 cm⁻¹; Anal. Calcd for C₂₁H₂₃F₄NO₂: C, 63.47; H, 5.83; N,3.52. Found: C, 63.33; H, 5.74; N, 3.50.

Example 17N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-2,4,6-trimethylbenzamideN-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-2,4,6-trimethylbenzamide

In the same manner as in Example 1 4), the objective substance (0.48 g,36%) was obtained as crystals.

mp 141-143° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 2.08 (6H, s), 2.25 (3H, s),3.14 (1H, dd, J=7.2 Hz, 14.0 Hz), 3.36 (1H, dd, J=6.2 Hz, 14.0 Hz),6.07-6.18 (1H, m), 6.37 (1H, br d, J=8.4 Hz), 6.80 (2H, s), 7.18 (2H, t,J=8.4 Hz), 7.24-7.31 (2H, m), 7.50 (2H, d, J=8.0 Hz), 8.01-8.11 (2H, m);IR (KBr) 3237, 1694, 1634 cm⁻¹; Anal. Calcd for C₂₆H₂₃F₄NO₂: C, 68.26;H, 5.07; N, 3.06. Found: C, 68.23; H, 5.25; N, 2.91.

2)N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-2,4,6-trimethylbenzamide

In the same manner as in Example 1 5), the objective substance (325 mg,92%, (1RS,2SR) form/(1RS,2RS) form=1/10) was obtained as an amorphouscompound.

¹H-NMR (CDCl₃, 200 MHz) δ 1.86 (6H, s), 2.22 (3H, s), 3.03 (1H, dd,J=7.3 Hz, 13.9 Hz), 3.12 (1H, dd, J=7.6 Hz, 13.4 Hz), 3.15-3.28 (1H, m),4.58 (1H, ddd, J=3.5 Hz, 7.8 Hz, 15.8 Hz), 4.70 (1H, br s), 6.01 (1H, brd, J=9.2 Hz), 6.73 (2H, s), 6.94-7.13 (2H, m), 7.22-7.31 (2H, m), 7.45(2H, d, J=8.4 Hz), 7.58 (2H, d, J=8.0 Hz); IR (KBr) 3268, 1620 cm⁻¹;Anal. Calcd for C₂₆H₂₅F₄NO₂: C, 67.96; H, 5.48; N, 3.05. Found: C,67.80; H, 5.74; N, 3.04.

Example 182-fluoro-N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzamide

1)2-fluoro-N-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzamide

In the same manner as in Example 1 4), the objective substance (136 mg,90%) was obtained as crystals.

mp 109-111° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 3.22 (1H, dd, J=5.2 Hz, 13.6Hz), 3.46 (1H, dd, J=6.2 Hz, 13.4 Hz), 5.98-6.11 (1H, m), 7.09-7.33 (6H,m), 7.43-7.69 (4H, m), 7.97-8.11 (3H, m); IR (KBr) 3439, 1686, 1655cm⁻¹; Anal. Calcd for C₂₃H₁₆F₅NO₂: C, 63.74; H, 3.72; N, 3.23. Found: C,63.56; H, 3.66; N, 3.40.

2)2-fluoro-N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzamide

In the same manner as in Example 1 5), the objective substance (367 mg,68%, (1RS,2SR) form/(1RS,2RS) form=1/2) was obtained as crystals.

mp 115-117° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 3.00-3.22 (3H, m), 4.42-4.58(1H, m), 4.82 (1H, m), 6.92-7.60 (12H, m); IR (KBr) 3447, 3333, 1644cm⁻¹; Anal. Calcd for C₂₃H₁₈F₅NO₂: 63.45; H, 4.17; N, 3.22. Found: C,63.45; H, 4.22; N, 3.15.

Example 194-tert-butyl-N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzamide

1)4-tert-butyl-N-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzamide

In the same manner as in Example 1 4), the objective substance (1.06 g,78%) was obtained as crystals.

mp 58° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 1.34 (9H, s), 3.21 (1H, dd, J=5.6Hz, 14.0 Hz), 3.48 (1H, dd, J=6.6 Hz, 14.0 Hz), 6.03 (1H, ddd, J=4.8 Hz,5.6 Hz, 6.6 Hz), 7.04-7.26 (5H, m), 7.41-7.50 (4H, m), 7.68-7.75 (2H,m), 7.97-8.08 (2H, m); IR (KBr) 3299, 1694 cm⁻¹; Anal. Calcd forC₂₇H₂₅F₄NO₂.0.1H2O: C, 68.52; H, 5.37; N, 2.96. Found: C, 68.33; H,5.22; N, 2.92.

2)4-tert-butyl-N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzamide

In the same manner as in Example 1 5), the objective substance (0.50 g,97%, (1RS,2SR) form/(1RS,2RS) form=3/2) was obtained as an amorphouscompound.

¹H-NMR (CDCl₃, 200 MHz) δ 1.31 (9H, s), 2.90-2.95 (2H×3/5, m), 3.14(2H×2/5, d, J=7.4 Hz), 3.64 (1H×2/5, d, J=3.4 Hz), 3.83 (1H×3/5, d,J=3.4 Hz), 4.37 (2H×2/5, ddd, J=3.2 Hz, 7.2 Hz, 15.6 Hz), 4.53-4.68(1H×3/5, m), 4.83 (1H×2/5, t, J=4.0 Hz), 5.06 (1H×3/5, t, J=6.6 Hz),6.13 (1H×3/5, d, J=8.2 Hz), 6.37 (1H×2/5, d, J=8.4 Hz), 6.92-7.13 (2H,m), 7.21-7.32 (2H, m), 7.36-7.59 (8H, m); IR (KBr) 3301, 1620 cm⁻¹;Anal. Calcd for C₂₇H₂₇F₄NO₂.0.2H₂O: C, 67.97; H, 5.79; N, 2.94. Found:C, 67.97; H, 5.80; N, 2.89.

Example 20N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-4-phenylbenzamide

1)N-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-4-phenylbenzamide

In the same manner as in Example 1 4), the objective substance (1.24 g,88%) was obtained as crystals.

mp 169° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 3.24 (1H, dd, J=4.6 Hz, 14.0 Hz),3.52 (1H, dd, J=6.4 Hz, 14.0 Hz), 6.04 (1H, ddd, J=4.6 Hz, 5.2 Hz, 6.4Hz), 7.07-7.25 (5H, m), 7.38-7.52 (5H, m), 7.58-7.72 (4H, m), 7.86 (2H,d, J=8.8 Hz), 7.99-8.10 (2H, m); IR (KBr) 3291, 1688, 1645 cm⁻¹; Anal.Calcd for C₂₉H₂₁F₄NO₂: C, 70.87; H, 4.31; N, 2.85. Found: C, 70.89; H,4.23; N, 2.86.

2)N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-4-phenylbenzamide

In the same manner as in Example 1 5), the objective substance (0.49 g,96%, (1RS,2SR) form/(1RS,2RS) form=3/2) was obtained as crystals.

mp 178-185° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 2.93-3.00 (2H×3/5, m), 3.17(2H×2/5, d, J=7.6 Hz), 3.36 (1H×2/5, d, J=4.4 Hz), 3.63 (1H×3/5, d,J=3.2 Hz), 4.35-4.52 (1H×2/5, m), 4.55-4.71 (1H×3/5, m), 4.87 (1H×2/5,t, J=3.9 Hz), 5.11 (1H×3/5, t, J=3.6 Hz), 6.17 (1H×3/5, d, J=8.6 Hz),6.42 (1H×2/5, d, J=8.0 Hz), 6.95-7.13 (2H, m), 7.24-7.68 (15H, m); IR(KBr) 3304, 1634 cm⁻¹; Anal. Calcd for C₂₉H₂₃F₄NO₂: C, 70.58; H, 4.70;N, 2.84. Found: C, 70.53; H, 4.72; N, 2.72.

Example 21N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-3-pyridinecarboxamide

1)N-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-3-pyridinecarboxamide

In the same manner as in Example 1 4), the objective substance (0.74 g,62%) was obtained as crystals.

mp 137-138° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 3.23 (1H, dd, J=5.0 Hz, 13.8Hz), 3.49 (1H, dd, J=6.6 Hz, 14.0 Hz), 5.98-6.07 (1H, m), 7.06-7.26 (5H,m), 7.37-7.43 (1H, m), 7.47 (2H, d, J=8.4 Hz), 7.98-8.11 (3H, m), 8.76(1H, dd, J=1.8 Hz, 4.8 Hz), 9.00 (1H, dd, J=0.8 Hz, 2.2 Hz); IR (KBr)3287, 1694, 1661 cm⁻¹; Anal. Calcd for C₂₂H₁₆F₄N₂O₂: C, 63.46; H, 3.87;N, 6.73. Found: C, 63.19; H, 4.03; N, 6.68.

2)N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]-3-pyridinecarboxamide

In the same manner as in Example 1 5), the objective substance (0.43 g,86%, (1RS,2SR) form/(1RS,2RS) form=5/2) was obtained as crystals.

mp 160-165° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 2.95 (2H×5/7, br s), 3.10(1H×2/7, br s), 3.16 (2H×2/7, d, J=7.0 Hz), 3.35 (1H×5/7, br s),4.43-4.75 (1H, m), 4.86 (1H×2/7, br s), 5.10 (1H×5/7, br s), 6.25(1H×5/7, br d, J=8.6 Hz), 6.48 (1H×2/7, br d, J=8.8 Hz), 6.95-7.16 (2H,m), 7.21-7.62 (7H, m), 7.87-7.95 (1H, m), 8.66-8.80 (2H, m); IR (KBr)3324, 3142, 1644 cm⁻¹; Anal. Calcd for C₂₂H₁₈F₄N₂O₂: C, 63.16; H, 4.34;N, 6.70. Found: C, 62.97; H, 4.24; N, 6.51.

Example 22N-(2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-oxo-4H-pyran-2-carboxamideandN-(2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-hydroxytetrahydro-2H-pyran-2-carboxamide

1) To a solution of1-(4-fluorophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (600 mg, 1.73 mmol) and 4-oxo-4H-pyran-2-carboxylic acid(266 mg, 1.90 mmol) in N,N-dimethylformamide (10 ml) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (496 mg,2.59 mmol), 1-hydroxy-1H-benzotriazole (396 mg, 2.59 mmol) and1,8-diazabicyclo[5.4.0]-7-undecene (0.28 ml, 1.90 mmol) and the mixturewas stirred overnight. To the reaction solution were added 1N aqueoushydrochloric acid solution (10 ml) and water (100 ml) and the mixturewas extracted with ethyl acetate (50 ml×2). The extract was washed with1N aqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethyl acetate)and recrystallized from ethyl acetate-hexane to giveN-(2-(4-fluorophenyl)-2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-oxo-4H-pyran-2-carboxamide(570 mg, 76%).

mp 115-116° C. IR ν max^(KBr)cm⁻¹: 1661, 1620, 1597, 1510, 1412. Anal.Calcd for C₂₂H₁₅F₄NO₄.0.1H₂O: C, 60.72; H, 3.52; N, 3.22. Found: C,60.60; H, 3.55; N, 3.24. ¹H-NMR (CDCl₃)δ: 3.23 (1H, dd, J=14.0, 5.2 Hz),3.43 (1H, dd, J=14.0, 5.2 Hz), 5.93 (1H, q, J=6.4 Hz), 6.44 (1H, dd,J=5.8, 2.6 Hz), 7.07 (2H, d, J=8.0 Hz), 7.10-7.26 (2H, m), 7.48 (2H, d,J=8.0 Hz), 7.59 (1H, d, J=7.4 Hz), 7.77 (1H, d, J=6.0 Hz), 7.92-8.06(2H, m).

2) To a solution ofN-(2-(4-fluorophenyl)-2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-oxo-4H-pyran-2-carboxamide(400 mg, 0.92 mmol) in methanol (30 ml) was added manganese (II)chloride (232 mg, 1.85 mmol), and the mixture was stirred at roomtemperature for 30 min. To the reaction solution was added sodiumborohydride (70 mg, 1.85 mmol) under ice-cooling and the mixture wasstirred for 1 hr. The reaction solution was poured into 1N hydrochloricacid (30 ml), and extracted with ethyl acetate (50 ml×2). The extractwas washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate). High polarfractions were collected and concentrated, and the obtained crudecrystal was washed with hexane to giveN-(2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-oxo-4H-pyran-2-carboxamide((1RS,2SR)form: (1RS,2RS) form=3:2, 139 mg, 35%).

IR ν max^(KBr)cm⁻¹: 1659, 1607, 1512, 1416. Anal. Calcd forC₂₂H₁₇F₄NO₄.0.1H₂O: C, 60.44; H, 3.97; N, 3.20. Found: C, 61.24; H,3.93; N, 3.03. ¹H-NMR (CDCl₃)δ: 2.60-2.82 (1H, m), 2.90-2.96 (1H, m),3.04-3.20 (1H, m), 4.40-4.70 (1H, m), 4.78-4.84 (2/5H, m), 5.02-5.10(3/5H, m), 6.36-6.42 (1H, m), 6.70-7.80 (11H, m).

Simultaneously, less polar fractions were collected and concentrated togiveN-(2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-hydroxytetrahydro-2H-pyran-2-carboxamide((1RS,2SR)form: (1RS,2RS) form=7:3, 139 mg, 35%) as an amorphous compound.

IR ν max^(KBr)cm⁻¹: 1645, 1510. Anal. Calcd for C₂₂H₂₃F₄NO₄: C, 59.86;H, 5.25; N, 3.17. Found: C, 60.02; H, 5.01; N, 3.04. ¹H-NMR (CDCl₃)δ:1.70-2.00 (3H, m), 2.70-3.40 (3H, m), 3.70-4.60 (4H, m), 4.68-4.78(0.3H, m), 4.92-5.04 (0.7H, m), 6.00 (0.3H, d, J=4.8 Hz), 6.05 (0.7H, d,J=4.6 Hz), 4.58-6.70 (0.7H, m), 6.76-6.90 (0.3H, m), 6.95-7.60 (8H, m).

Example 234-fluoro-N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzenesulfonamide

1)4-fluoro-N-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzenesulfonamide

To a solution of2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethylaminehydrochloride (1.0 g, 2.88 mmol) in N,N-dimethylformamide, (10 ml) wereadded 4-fluorobenzenesulfonyl chloride (0.84 g, 4.32 mmol) and1,8-diazabicyclo[5.4.0]-7-undecene (1.3 ml, 8.64 mmol) and the mixturewas stirred for 4 hrs. The reaction solution was extracted with ethylacetate. The extract was washed successively with water and saturatedbrine, dried over magnesium sulfate and concentrated under reducedpressure. The residue was recrystallized from ethyl acetate-hexane togive the objective substance (1.02 g, 76%) as crystals.

mp 209-210° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 2.96 (1H, dd, J=6.6 Hz, 14.0Hz), 3.20 (1H, dd, J=5.6 Hz, 14.6 Hz), 5.05-5.18 (1H, m), 5.62 (1H, brd, J=6.4 Hz), 7.00 (2H, t, J=8.6 Hz), 7.04-7.20 (4H, m), 7.45 (2H, d,J=8.0 Hz), 7.65-7.72 (2H, m), 7.77-7.84 (2H, m); IR (KBr) 3229, 1676,1595 cm⁻¹; Anal. Calcd for C₂₂H₁₆F₅NO₃S: C, 56.29; H, 3.44; N, 2.98.Found: C, 56.15; H, 3.46; N, 3.26.

2)4-fluoro-N-[2-(4-fluorophenyl)-2-hydroxy-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzenesulfonamide

To a solution of4-fluoro-N-[2-(4-fluorophenyl)-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]ethyl]benzenesulfonamide(0.5 g, 1.07 mmol) in methanol (5 ml) was added sodium borohydride (45mg, 1.19 mmol) under ice-cooling and the mixture-was stirred for 1 hr.1N Hydrochloric acid was added to the reaction solution and the mixturewas stirred at room temperature for 10 min. The reaction solution wasextracted with ethyl acetate. The extract was washed successively withwater and saturated brine, dried over magnesium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane=1/2) to give the objectivesubstance (0.45 g, 89%, ⅓ mixture of isomers) as crystals.

mp 141-161° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 2.30 (3/4H, d, J=3.4 Hz),2.52-2.79 (6/4H, m), 3.13 (3/4H, dd, J=7.0 Hz, 14.0 Hz), 3.59 (1H, ddd,J=3.6 Hz, 7.4 Hz, 15.8 Hz), 4.75-4.83 (7/4H, m), 5.08-5.13 (1/4H, m),6.83-7.00 (4H, m), 7.04-7.22 (4H, m), 7.29-7.49 (4H, m); IR (KBr) 3482,3293 cm⁻¹

Example 241,1-dimethylethyl(1RS,2RS)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethylcarbamate

1) To a solution of 4′-fluoroacetophenone (57.8 g, 0.307 mol) andethanol (1 ml) in diethyl carbonate (300 ml) was added sodium hydride(24.5 g, 60% in oil, 0.63 mol) by small portions. Because heat isgradually generated, the mixture was ice-cooled and stirred at roomtemperature for 2 hrs. To the reaction solution was added 6Nhydrochloric acid to quench the reaction. Water (300 ml) was added andthe mixture was extracted with ethyl acetate. The extract was washedwith water, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=50:1-5:1) to give ethyl3-(4-fluorophenyl)-3-oxopropionate (71.2 g, 89%).

IR ν max^(KBr)cm⁻¹: 1744, 1696, 1431, 1325, 1202, 1132, 1069, 1017, 853.¹H-NMR (CDCl₃)δ: 1.28 (3H×0.62, t, J=7.8 Hz), 1.37 (3H×0.38, t, J=7.8Hz), 4.04 (2H×0.62, s), 4.25 (2H×0.62, q, J=7.8 Hz), 4.31 (2H×0.38, q,J=7.8 Hz), 5.75 (1H×0.38, s), 7.28 (1H×0.62, s), 7.70 (2H×0.38, d, J=8.0Hz), 7.78 (2H×0.62, d, J=8.0 Hz), 7.90 (2H×0.38, d, J=8.0 Hz), 8.08(2H×0.62, d, J=8.0 Hz).

2) To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (34.7 g,115.5 mmol) in acetonitrile (300 ml) were added 4-trifluoromethylbenzylbromide (27.6 g, 115.5 mmol) and potassium carbonate (31.9 g, 231 mmol),and the mixture was stirred at room temperature for 4 hrs. The reactionsolution was diluted with water (1 L) and extracted with ethyl acetate(500 ml×2). The extract was washed with water and saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.Hexane was added to the residue and the precipitated crystals werewashed with hexane to give ethyl3-(4-fluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate(31 g, 76%).

mp 56-57° C. IR ν max^(KBr)cm⁻¹: 1738, 1688, 1618, 1599, 1508. Anal.Calcd for C₁₉H₁₆F₄O₃: C, 61.96; H, 4.38 Found: C, 61.90; H, 4.43. ¹H-NMR(CDCl₃)δ: 1.16 (3H, t, J=6.8 Hz), 3.38 (2H, d, J=7.6 Hz), 4.14 (2H, q,J=6.8 Hz), 4.58 (1H, t, J=7.6 Hz), 7.04-7.20 (2H, m), 7.35 (2H, d, J=8.0Hz), 7.52 (2H, d, J=8.0 Hz), 7.92-8.08 (2H, m).

3) To a solution of ethyl3-(4-fluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate(6 g, 16.3 mmol) in methanol (100 ml) was added sodium borohydride (640mg, 16.9 mmol) under ice-cooling, and the mixture was stirred for 20min. The reaction solution was poured into 1N hydrochloric acid (50 ml),and extracted with ethyl acetate (100 ml×2). The extract was washed withwater and saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1) to give ethyl(2RS,3SR)-3-(4-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate(5.1 g, 84%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1728, 1607, 1510. Anal. Calcd for C₁₉H₁₈F₄O₃: C,61.62; H, 4.90. Found: C, 61.52; H, 4.88. ¹H-NMR (CDCl₃)δ: 0.99 (3H, t,J=7.4 Hz), 2.70-3.10 (3H, m), 3.13 (1H, d, J=6.2 Hz), 3.99 (2H, q, J=7.4Hz), 4.76-4.86 (1H, m), 6.98-7.16 (2H, m), 7.20-7.40 (4H, m), 7.52 (2H,d, J=8.0 Hz).

4) To a solution of ethyl(2RS,3SR)-3-(4-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate(4.85 g, 13.1 mmol) in methanol (20 ml) was added 1N aqueous sodiumhydroxide solution (13.1 ml, 13.1 mmol), and the mixture was stirred atroom temperature for 6 hrs. The reaction solution was evaporated underreduced pressure, diluted with 1N hydrochloric acid (50 ml), andextracted with ethyl acetate (100 ml×2). The extract was washed withwater and saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give(2RS,3SR)-3-(4-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (3.8 g, 84%).

mp 136-139° C.; ¹H-NMR (CDCl₃, 200M Hz)δ2.75 (1H, dd, J=5.8 Hz, 13.4Hz), 2.95 (1H, dd, J=9.2 Hz, 13.2 Hz), 3.08 (2H, d, J=8.0 Hz), 4.82 (1H,d, J=7.0 Hz), 7.08 (2H, t, J=8.8 Hz), 7.22 (2H, d, J=8.0 Hz), 7.34 (2H,dd, J=5.3 Hz, 8.8 Hz); IR (KBr) 3351, 3500-2400, 1713 cm⁻¹; Anal. Calcdfor C₁₇H₁₄F₄O₃: C, 59.65; H, 4.12. Found: C, 59.52; H, 4.17.

5) To a solution of(2RS,3SR)-3-(4-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (3.75 g, 11.0 mmol) in tetrahydrofuran (70 ml) were addeddiphenylphosphoryl azide (2.6 ml, 12.1 mmol) and triethylamine (2.30 ml,16.4 mmol) and the mixture was heated under reflux for 3 hrs. Thereaction solution was diluted with water (300 ml), and extracted withethyl acetate (200 ml×2). The extract was washed with saturated brine,dried over anhydrous magnesium sulfate and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=2:1-1:1) and recrystallized from ethylacetate-hexane to give(4RS,5RS)-5-(4-fluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(3.28 g, 88%).

mp 83-84° C. IR ν max^(KBr)cm⁻¹: 1755, 1609, 1514, 1420, 1387. Anal.Calcd for C₁₇H₁₃F₄NO₂: C, 60.18; H, 3.86; N, 4.13. Found: C, 60.08; H,3.56; N, 4.10. ¹H-NMR (CDCl₃)δ: 2.90-3.16 (2H, m), 3.95 (1H, dd, J=12.8,6.2 Hz), 5.19 (1H, d, J=6.2 Hz), 5.73 (1H, brs), 7.00-7.12 (2H, m),7.12-7.40 (4H, m), 7.60 (2H, d, J=8.0 Hz).

6) To a solution of(4RS,5RS)-5-(4-fluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(3.19 g, 9.41 mmol) in acetonitrile (30 ml) were added di-t-butyldicarbonate (2.46 g, 11.29 mmol) and 4-dimethylaminopyridine (114 mg,0.94 mmol) and the mixture was stirred at room temperature for 1 hr. Thereaction solution was diluted with water (100 ml), and extracted withethyl acetate (100 ml×2). The extract was washed with saturated brine,dried over anhydrous magnesium sulfate and evaporated under reducedpressure. Recrystallization from ethyl acetate-hexane gave1,1-dimethylethyl(4RS,5RS)-5-(4-fluorophenyl)-2-oxo-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidine-3-carboxylate(3.84 g, 93%).

mp 126-127° C. IR ν max^(KBr)cm⁻¹: 1817, 1724, 1514, 1325. Anal. Calcdfor C₂₂H₂₁F₄NO₄: C, 60.14; H, 4.82; N, 3.19. Found: C, 60.05; H, 5.12;N, 3.11. ¹H-NMR (CDCl₃)δ: 1.58 (9H, s), 3.01 (1H, dd, J=13.2, 9.8 Hz),3.51 (1H, dd, J=13.2, 3.6 Hz), 4.26-4.38 (1H, m), 5.13 (1H, d, J=2.6Hz), 6.80-7.04 (4H, m), 7.38 (2H, d, J=8.0 Hz), 7.65 (2H, d, J=8.0 Hz).

7) To a solution of 1,1-dimethylethyl(4RS,5RS)-5-(4-fluorophenyl)-2-oxo-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidine-3-carboxylate(3.7 g, 8.42 mmol) in methanol (20 ml) was gradually added a solution ofsodium hydroxide (0.40 g, 10.10 mmol) in methanol (20 ml) underice-cooling. The reaction solution was stirred for 1 hr, diluted with 1Nhydrochloric acid (15 ml) and water (100 ml), and extracted with ethylacetate (100 ml×2). The extract was washed with saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexaneto give the title compound (2.24 g, 64%).

mp 95-96° C. IR ν max^(KBr)cm⁻¹: 1688, 1510. Anal. Calcd forC₂₁H₂₃F₄NO₃: C, 61.01; H, 5.61; N, 3.39. Found: C, 60.92; H, 5.55; N,3.28. ¹H-NMR (CDCl₃)δ: 1.31 (9H, s), 2.80-3.10 (3H, m), 3.80-4.02 (1H,m), 4.62-4.80 (2H, m), 6.96-7.10 (2H, m), 7.22-7.40 (4H, m), 7.55 (2H,d, J=8.2 Hz).

Example 252-(ethyloxy)-N-((1RS,2RS)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

1) To a solution of1-(4-fluorophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (600 mg, 1.73 mmol) and 2-ethyloxy-1-naphthalenecarboxylicacid (411 mg, 1.90 mmol) in N,N-dimethylformamide (10 ml) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (496 mg,2.59 mmol), 1-hydroxy-1H-benzotriazole (396 mg, 2.59 mmol) and1,8-diazabicyclo[5.4.0]-7-undecene (0.28 ml, 1.90 mmol) and the mixturewas stirred overnight. To the reaction solution were added 1N aqueoushydrochloric acid solution (10 ml) and water (100 ml) and the mixturewas extracted with ethyl acetate (50 ml×2). The extract was washed with1N aqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure.Recrystallization from ethyl acetate-hexane gave2-(ethyloxy)-N-(2-(4-fluorophenyl)-2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide(670 mg, 76%).

mp 188-189° C. IR ν max^(KBr)cm⁻¹: 1688, 1634, 1597, 1508, 1325. Anal.Calcd for C₂₉H₂₃F₄NO₃: C, 68.36; H, 4.55; N, 2.75. Found: C, 68.25; H,4.58; N, 2.76. ¹H-NMR (CDCl₃)δ: 1, 24 (3H, t, J=7.0 Hz), 3.20 (1H, dd,J=14.0, 6.4 Hz), 3.46 (1H, dd, J=14.0, 6.4 Hz), 4.13 (2H, q, J=7.0 Hz),6.23 (1H, q, J=6.6 Hz), 6.96 (1H, d, J=8.4 Hz), 7.10-7.56 (9H, m),7.60-7.80 (2H, m), 7.85 (1H, d, J=9.0 Hz), 8.04-8.18 (2H, m).

2) To a solution of2-(ethyloxy)-N-(2-(4-fluorophenyl)-2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide(400 mg, 0.79 mmol) in methanol (30 ml) was added manganese (II)chloride (198 mg, 1.57 mmol), and the mixture was stirred at roomtemperature for 30 min. To the reaction solution was added sodiumborohydride (30 mg, 0.79 mmol) under ice-cooling, and the mixture wasstirred for 1 hr. The reaction solution was poured into 1N hydrochloricacid (30 ml), and extracted with ethyl acetate (50 ml×2). The extractwas washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethylacetate=2:1-1:1 and recrystallized from ethyl acetate-hexane to give thetitle compound (227 mg, 57%).

mp 186-187° C. IR ν max^(KBr)cm⁻¹: 1639, 1512, 1242, 1165. Anal. Calcdfor C₂₉H₂₅F₄NO₃: C, 68.09; H, 4.93; N, 2.74. Found: C, 68.04; H, 4.79;N, 2.85. ¹H-NMR (CDCl₃)δ: 1.37 (3H, t, 6.8 Hz), 2.84-3.28 (2H, m), 3.34(1H, d, J=3.8 Hz), 4.08-4.26 (2H, m), 4.60-4.84 (2H, m), 6.15 (1H, d,J=8.6 Hz), 6.96-7.16 (3H, m), 7.20-7.50 (7H, m), 7.58 (2H, d, J=8.4 Hz),7.76 (2H, dd, J=18.2, 9.2 Hz).

Example 26N-((1RS,2RS)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

1) To a solution of 1,1-dimethylethyl(1RS,2RS)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethylcarbamate(2.1 g, 5.08 mmol) in ethanol (25 ml) was added 20% hydrogen chlorideethanol solution (25 ml) and the mixture was heated under reflux for 1hr. The reaction solution was evaporated under reduced pressure, and theresidue was washed with diethyl ether to give(1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (1.7 g, 96%).

mp 166-167° C. IR ν max^(KBr)cm⁻¹: 1605, 1514, 1497. Anal. Calcd forC₁₆H₁₆ClF₄NO: C, 54.11; H, 4.71; N, 3.94. Found: C, 54.10; H, 4.62; N,3.83. ¹H-NMR (CD₃OD)δ: 2.98 (2H, d, J=7.4 Hz), 3.60-3.78 (1H, m), 4.63(1H, d, J=6.2 Hz), 7.04-7.16 (2H, m), 7.36-7.50 (4H, m), 7.61 (2H, d,J=8.4 Hz).

2) To a solution of(1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were added1-naphthoyl chloride (97 mg, 0.64 mmol) and saturated aqueous sodiumhydrogen carbonate (5 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (50 ml), andextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1-1:1), and recrystallized fromethyl acetate-hexane to give the title compound (145 mg, 72%).

mp 134-135° C. IR ν max^(KBr)cm⁻¹: 1634, 1510. Anal. Calcd forC₂₇H₂₁F₄NO₂: C, 69.37; H, 4.53; N, 3.00. Found: C, 69.08; H, 4.80; N,3.01. ¹H-NMR (CDCl₃)δ: 3.18-3.30 (3H, m), 4.54-4.72 (1H, m), 4.92 (1H,brs), 6.20 (1H, d, J=8.8 Hz), 6.96-7.14 (2H, m), 7.16-7.70 (11H, m),7.78-7.90 (2H, m).

Example 27N-((1RS,2RS)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-(trifluoromethyl)benzamide

To a solution of(1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were added4-trifluorobenzoyl chloride (96 mg, 0.64 mmol) and saturated aqueoussodium hydrogen carbonate (5 ml) and the mixture was stirred overnightat room temperature. The reaction solution was diluted with water (50ml) and extracted with ethyl acetate (50 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1) and recrystallizedfrom ethyl acetate-hexane to give the title compound (129 mg, 62%).

mp 162-163° C. IR ν max^(KBr)cm⁻¹: 1653, 1508, 1329. Anal. Calcd forC₂₄H₁₈F₇NO₂: C, 59.39; H, 3.74; N, 2.89. Found: C, 59.20; H, 4.01; N,2.91. ¹H-NMR (CDCl₃)δ: 3.18-3.30 (3H, m), 4.54-4.72 (1H, m), 4.92 (1H,brs), 6.20 (1H, d, J=8.8 Hz), 6.96-7.14 (2H, m), 7.16-7.70 (11H, m),7.78-7.90 (2H, m).

Example 28 1,1-dimethylethyl(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethylcarbamate

1) To a solution of ethyl3-(4-fluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate(20.8 g, 56.5 mmol) in methanol (500 ml) was added manganese (II)chloride (14.2 g, 113 mmol), and the mixture was stirred at roomtemperature for 30 min. To the reaction solution was added sodiumborohydride (4.28 g, 113 mmol) under ice-cooling, and the mixture wasstirred for 20 min. The reaction solution was poured into 1Nhydrochloric acid (300 ml) and extracted with ethyl acetate (500 ml×2).The extract was washed with water and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1) to give ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate(11.1 g, 53%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1726, 1618, 1607, 1510. Anal. Calcd for C₁₉H₁₈F₄O₃:C, 61.62; H, 4.90. Found: C, 61.62; H, 5.06. ¹H-NMR (CDCl₃)δ: 0.91 (3H,t, J=7.0 Hz), 2.88-3.10 (4H, m), 3.88 (2H, q, J=7.0 Hz), 4.98-5.06 (1H,m), 6.96-7.12 (2H, m), 7.20 (2H, d, J=8.0 Hz), 7.30-7.44 (2H, m), 7.49(2H, d, J=8.0 Hz).

2) To a solution of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate(11.0 g, 29.7 mmol) in methanol (90 ml) was added 1N aqueous sodiumhydroxide solution (59.6 ml, 59.6 mmol), and the mixture was stirred atroom temperature for 6 hrs. The reaction solution was evaporated underreduced pressure, diluted with 1N hydrochloric acid (100 ml), andextracted with ethyl acetate (200 ml×2). The extract was washed withwater and saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. Recrystallization from ethylacetate-hexane gave(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (8.6 g, 85%).

mp 111-112° C. IR ν max^(KBr)cm⁻¹: 1713, 1607, 1512. Anal. Calcd forC₁₇H₁₄O₃F₄: C, 59.65; H, 4.12. Found: C, 59.65; H, 4.07. ¹H-NMR(CDCl₃)δ: 2.08 (1H, s), 2.94-3.20 (3H, m), 5.04-5.10 (1H, m), 6.98-7.12(2H, m), 7.18 (2H, d, J=8.0 Hz), 7.30-7.42 (2H, m), 7.48 (2H, d, J=8.0Hz).

3) To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (4.30 g, 12.6 mmol) in tetrahydrofuran (80 ml) were addeddiphenylphosphoryl azide (3.0 ml, 13.8 mmol) and triethylamine (2.63 ml,18.8 mmol) and the mixture was heated under reflux for 4 hrs. Thereaction solution was diluted with water (300 ml) and extracted withethyl acetate (200 ml×2). The extract was washed with saturated brine,dried over anhydrous magnesium sulfate and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=2:1-1:1) and recrystallized from ethylacetate-hexane to give(4RS,5SR)-5-(4-fluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(3.55 g, 83%).

mp 154-155° C. IR ν max^(KBr)cm⁻¹: 1755, 1611, 1514, 1235. Anal. Calcdfor C₁₇H₁₃F₄NO₂: C, 60.18; H, 3.86; N, 4.13. Found: C, 60.20; H, 3.80;N, 4.21. ¹H-NMR (CDCl₃)δ: 2.20-2.44 (2H, m), 4.26 (1H, q, J=8.0 Hz),5.25 (1H, brs), 5.79 (1H, d, J=8.0 Hz), 7.06-7.20 (4H, m), 7.28-7.40(2H, m), 7.54 (2H, d, J=8.0 Hz).

4) To a solution of(4RS,5SR)-5-(4-fluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(3.50 g, 10.32 mmol) in acetonitrile (30 ml) were added di-t-butyldicarbonate (2.70 g, 12.39 mmol) and 4-dimethylaminopyridine (126 mg,1.03 mmol) and the mixture was stirred at room temperature for 1 hr. Thereaction solution was diluted with water (100 ml) and extracted withethyl acetate (100 ml×2). The extract was washed with saturated brine,dried over anhydrous magnesium sulfate and evaporated under reducedpressure. Recrystallization from ethyl acetate-hexane gave1,1-dimethylethyl(4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidine-3-carboxylate(4.09 g, 90%).

mp 155-156° C. IR ν max^(KBr)cm⁻¹: 1821, 1724, 1514, 1360. Anal. Calcdfor C₂₂H₂₁F₄NO₄: C, 60.14; H, 4.82; N, 3.19. Found: C, 60.16; H, 4.84;N, 3.25. ¹H-NMR (CDCl₃)δ: 1.48 (9H, s), 2.61 (1H, dd, J=14.2, 8.4 Hz),2.91 (1H, dd, J=14.2, 5.2 Hz), 4.80 (1H, dd, J=8.4, 7.0 Hz), 5.68 (1H,d, J=7.0 Hz), 6.82 (2H, d, J=8.0 Hz), 6.92-7.06 (2H, m), 7.10-7.24 (2H,m), 7.36 (2H, d, J=8.0 Hz).

5) To a solution of 1,1-dimethylethyl(4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidine-3-carboxylate(4.0 g, 9.10 mmol) in methanol (22 ml) was gradually added a solution ofsodium hydroxide (0.44 g, 10.92 mmol) in methanol (22 ml) underice-cooling. The reaction solution was stirred for 3 hrs., diluted with1N hydrochloric acid (12 ml) and water (100 ml), and extracted withethyl acetate (100 ml×2). The extract was washed with saturated brine,dried over anhydrous magnesium sulfate and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexaneto give the title compound (2.90 g, 77%).

mp 158-159° C. IR ν max^(KBr)cm⁻¹: 3358, 1682, 1532, 1514. Anal. Calcdfor C₂₁H₂₃F₄NO₃: C, 61.01; H, 5.61; N, 3.39. Found: C, 60.95; H, 5.59;N, 3.20. ¹H-NMR (CDCl₃)δ: 1.32 (9H, s), 2.60-2.90 (2H, m), 3.11 (1H,brs), 4.00-4.20 (1H, m), 4.58 (1H, d, J=8.4 Hz), 4.92 (1H, s), 7.02-7.14(2H, m), 7.22 (2H, d, J=8.0 Hz), 7.32-7.44 (2H, m), 7.51 (2H, d, J=8.0Hz).

Example 29N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1) 6,7-dihydro-5H-benzo[a]cyclohepten-1-ylmethanol

To a solution oftert-butyl(6,7-dihydro-5H-benzo[a]cyclohepten-1-ylmethoxy)dimethylsilane(see Tetrahedron, 53, 15969-15982 (1990))(1.079 g, 3.740 mmol) intetrahydrofuran (30 ml) was added a 1.0 M solution (3.74 ml, 3.74 mmol)of tetrabutylammonium fluoride in tetrahydrofuran, and the mixture wasstirred at room temperature for 15 min. The reaction solution wasconcentrated and the obtained crude product was purified by silica gelcolumn chromatography (hexane/ethyl acetate=6/1−1/1) to give theobjective substance.

colorless liquid yield 0.573 g, 88% ¹H-NMR (CDCl₃, 200 MHz) δ 1.99-2.25(4H, m), 2.71 (2H, t, J=6.0 Hz), 4.73 (2H, s), 6.18 (1H, td, J=5.5 Hz,11.6 Hz), 6.73 (1H, d, J=11.6 Hz), 7.11-7.25 (3H, m); IR (neat) 3330,2930, 1449, 1067, 1020, 995, 772 cm⁻¹

2) 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid

To a solution of 6,7-dihydro-5H-benzo[a]cyclohepten-1-ylmethanol (31.41g, 180.3 mmol) in acetone (500 ml) was slowly added dropwise a solutionof chromic anhydride (36.1 g, 361 mmol) and conc. sulfuric acid (30 ml)dissolved in water (120 ml) under-ice-cooling. After the completion ofthe dropwise addition, the mixture was stirred at room temperature for 1hr. The reaction solution was again ice-cooled, and after addingisopropanol (60 ml), the mixture was stirred as it was for 0.5 hr.Acetone in the reaction solution was evaporated under reduced pressure.The residue was diluted with ethyl acetate, washed three times withwater and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the obtained residue wascrystallized from cold diisopropyl ether to give the objectivesubstance.

white crystal yield 19.78 g, 58% mp 146-147° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.08-2.16 (4H, m), 2.70 (2H, t, J=6.4 Hz), 6.24 (1H, td, J=6.4 Hz,11.1 Hz), 7.14 (1H, d, J=11.4 Hz), 7.23 (1H, t, J=7.3 Hz), 7.39 (1H, d,J=7.2 Hz), 7.92 (1H, dd, J=1.5 Hz, 7.7 Hz); IR (KBr) 3065-2530, 1686,1451, 1414, 1300, 1277, 926, 779 cm⁻¹; Anal. Calcd for C₁₂H₁₂O₂.0.1H₂O:C, 75.85; H, 6.47. Found: C, 75.88; H, 6.35.

3)(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol

(4RS,5SR)-5-(4-Fluorophenyl)-4-[4-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one(18.75 g, 55.26 mmol) and sodium hydroxide (8.84 g, 221 mmol) wereheated under reflux in ethanol (100 ml)-water (10 ml) for 5 hrs. Thereaction solution was diluted with water and extracted twice with ethylacetate. The collected organic-layer was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel (APS type) column chromatography(hexane/ethyl acetate=1/1-ethyl acetate) and crystallized from diethylether-hexane to give the objective substance.

white crystal yield 16.38 g, 95% mp 87-88° C.; ¹H-NMR (CDCl₃, 200 MHz) δ1.60 (2H, br s), 2.43 (1H, dd, J=10.2 Hz, 13.6 Hz), 2.87 (1H, dd, J=3.1Hz, 13.7 Hz), 3.29 (1H, ddd J=3.3 Hz, 5.2 Hz, 10.3 Hz), 4.66 (1H, d,J=5.0 Hz), 7.08 (2H, t, J=8.7 Hz), 7.27 (2H, d, J=8.0 Hz), 7.38 (2H, dd,J=5.4 Hz, 8.4 Hz), 7.55 (2H, d, J=7.6 Hz); IR (neat) 3360-2865, 1508,1325, 1225, 1163, 1121, 1067, 826 cm⁻¹; Anal. Calcd for C₁₆H₁₅F₄NO: C,61.34; H, 4.83; N, 4.47. Found: C, 61.32; H, 4.62; N, 4.48.

4)N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.157 g, 0.501 mmol), 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylicacid (94 mg, 0.50 mmol) and 1-hydroxybenzotriazole hydrate (77 mg, 0.50mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.50mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white crystal yield 0.134 g, 55% mp 197-198° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 1.91-2.04 (2H, m), 2.17-2.27 (2H, m), 2.65 2.70 (2H, m),2.83-3.00 (2H, m), 4.62-4.76 (1H, m), 4.97 (1H, t, J=4.0 Hz), 5.04 (1H,d, J=3.8 Hz), 5.84 (1H, td, J=5.1 Hz, 12.2 Hz), 6.11 (1H, d, J=12.0 Hz),6.81 (1H, d, J=8.8 Hz), 6.91 (1H, dd, J=1.9 Hz, 7.3 Hz), 7.01-7.14 (4H,m), 7.31 (2H, d, J=8.2 Hz), 7.47-7.54 (4H, m); IR (KBr) 3279, 2940,1640, 1534, 1514, 1325, 1229, 1163, 1121, 1069, 831 cm⁻¹; Anal. Calcdfor C₂₈H₂₅F₄NO₂: C, 69.56; H, 5.21; N, 2.90. Found: C, 69.41; H, 5.15;N, 2.91.

Example 304-fluoro-N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

1) To a solution of 1,1-dimethylethyl(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethylcarbamate(2.58 g, 6.24 mmol) in ethanol (35 ml) was. added 20% hydrogen chlorideethanol solution (35 ml) and the mixture was heated under reflux for 30min. The reaction solution was evaporated under reduced pressure and theresidue was washed with diethyl ether. to give(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (2.05 g, 94%).

mp 173-174° C. IR ν max^(KBr)cm⁻¹: 3314, 3009, 1611, 1512, 1331. Anal.Calcd for C₁₆H₁₆ClF₄NO.0.5H₂O: C, 53.57; H, 4.78; N, 3.90. Found: C,53.81; H, 4.81; N, 3.74. ¹H-NMR (DMSO-d₆)δ: 2.79 (2H, d, J=6.6 Hz),3.64-3.80 (1H, m), 5.03 (1H, s), 6.30 (1H, d, J4.0 Hz), 7.10-7.24 (2H,m), 7.33 (2H, d, J=8.0 Hz), 7.38-7.50 (2H, m), 7.59 (2H, d, J=8.0 Hz),8.07 (2H, brs).

2) To a solution of 4-fluoro-1-naphthalenecarboxylic acid (163 mg), 0.86mmol) in tetrahydrofuran (5 ml) were added oxalyl chloride (0.15 ml,1.72 mmol) and N,N-dimethylformamide (0.01 ml), and the mixture wasstirred at room temperature for 30 min. The reaction solution wasevaporated under reduced pressure. To a solution of the residue in ethylacetate (5 ml) were added(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (200 mg, 0.57 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml) and the mixture was stirred at room temperature for 2hrs. The reaction solution was diluted with water (50 ml), and extractedwith ethyl acetate (50 ml×2). The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1) and recrystallized from ethylacetate-hexane to give the title compound (214 mg, 77%).

mp 210-211° C. IR ν max^(KBr)cm⁻¹: 3275, 1642, 1626, 1601. Anal. Calcdfor C₂₇H₂₀F₅NO₂: C, 66.80; H, 4.15; N, 2.89. Found: C, 66.79; H, 4.19;N, 2.82. ¹H-NMR (CDCl₃)δ: 2.80-3.16 (2H, m), 3.18 (1H, d, J=3.6 Hz),4.72-4.94 (1H, m), 5.08-5.16 (1H, m), 5.92 (1H, d, J=8.2 Hz), 7.00-7.70(13H, m), 8.09 (1H, d, J=8.0 Hz).

Example 314-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide

1) methyl 4-amino-5,6,7,8-tetrahydronaphthalene-1-carboxylate

A solution of methyl 4-nitro-5,6,7,8-tetrahydronaphthalene-1-carboxylate(see Chem. Abstr., 43, 202f (1949), Chem. Abstr., 43, 202b (1949))(1.816 g, 7.720 mmol) in methanol (30 ml) was hydrogenated under normaltemperature and normal pressure using 10% palladium/carbon (containingwater by 50%) (0.5 g) as a catalyst until the starting materialdisappeared. The catalyst was filtered off and the filtrate was passedthrough a short silica gel column chromatography. The solvent wasevaporated under reduced pressure to give the objective substance.

yellow crystal yield 1.574 g, 99%

Recrystallization from ethyl acetate-hexane gave pale-yellow crystals.

mp 120-121° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 1.68-1.90 (4H, m), 2.44 (2H,t, J=6.2 Hz), 3.10 (2H, t, J=6.0 Hz), 3.81 (3H, s), 3.92 (2H, br s),6.50 (1H, d, J=8.4 Hz), 7.69 (1H, d, J=8.4 Hz); IR (KBr) 3486, 3374,2948, 2930, 2868, 1688, 1626, 1590, 1481, 1449, 1431, 1310, 1267, 1253,1196, 1142, 775 cm⁻¹; Anal. Calcd for C₁₂H₁₅NO₂: C, 70.22; H, 7.37; N,6.82. Found: C, 70.25; H, 7.33; N, 6.67.

2) methyl 4-fluoro-5,6,7,8-tetrahydronaphthalene-1-carboxylate

While stirring methyl4-amino-5,6,7,8-tetrahydronaphthalene-1-carboxylate (1.210 g, 5.895mmol) and conc. hydrochloric acid (2 ml) in water (20 ml), a solution ofsodium nitrite (0.49 g, 7.07 mmol) in water (1 ml) was added dropwiseunder ice-cooling and the mixture was stirred at said temperature for 10min. To the reaction solution was added a 60% aqueoushexafluorophosphoric acid solution (1.48 ml, 10.0 mmol) with vigorousstirring under ice-cooling and the mixture was stirred as it was for 0.5hr. The resulting precipitate was filtered, washed with water andmethanol-diethyl ether (1:4) and dried to give diazonium salt as a whitepowder. The obtained diazonium salt was heated in liquid paraffin (8 ml)at 170° C. for. 0.5 hr. The mixture was cooled to room temperature andaqueous sodium hydrogen carbonate solution was added. The mixture wasextracted twice with ethyl acetate. The collected organic layer wasdried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained crude product was purified bysilica gel column chromatography (hexane/ethyl acetate=200/1-15/1) togive the objective substance.

white crystal yield 0.487 g, 40% mp 44-45° C.; ¹H-NMR (CDCl₃, 200 MHz) δ1.72-1.83 (4H, m), 2.74 (2H, br s), 3.08 (2H, br s), 3.86 (3H, s), 6.87(1H, t, J=8.6 Hz), 7.73 (1H, dd, J=6.0 Hz, 8.6 Hz); IR (KBr) 2944, 1721,1582, 1472, 1433, 1260, 1254, 1190, 1157, 1130, 1038, 770 cm⁻¹; Anal.Calcd for C₁₂H₁₃FO₂: C, 69.22; H, 6.29. Found: C, 69.39; H, 6.43.

3) 4-fluoro-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid

To a solution of methyl4-fluoro-5,6,7,8-tetrahydronaphthalene-1-carboxylate (0.434 g, 2.084mmol) in methanol (10 ml)-tetrahydrofuran (10 ml) was added 1N aqueoussodium hydroxide solution (4.17 ml, 4.17 mmol), and the mixture wasstirred overnight at room temperature. The reaction solution wasconcentrated, diluted with water, acidified with 1N hydrochloric acid,and extracted twice with ethyl acetate. The collected organic layer wasdried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was crystallized from diethylether-hexane to give the objective substance.

white crystal yield 0.308 g, 76% mp 172-173° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.74-1.82 (4H, m), 2.76 (2H, br s), 3.16 (2H, br s), 6.91 (1H, t,J=8.8 Hz), 7.91 (1H, dd, J=6.1 Hz, 8.5 Hz); IR (KBr) 3100-2600, 1686,1588, 1429, 1304, 1273, 1250, 1188 cm⁻¹; Anal. Calcd for C₁₁H₁₁FO₂: C,68.03; H, 5.71. Found: C, 68.10; H, 6.00.

4)4-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.164 g, 0.523 mmol),4-fluoro-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid (0.10 g, 0.52mmol) and 1-hydroxybenzotriazole hydrate (80 mg, 0.52 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.10 g, 0.52 mmol) was added, and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen-carbonate solution,dried over anhydrous magnesium sulfate, and passed through silica gel.The solvent was evaporated under reduced pressure and the obtainedresidue was crystallized from ethyl acetate-diisopropyl ether-hexane togive the objective substance.

white crystal yield 0.220 g, 86% mp 241-242° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 1.53-1.75 (4H, m), 2.11-2.26 (1H, m), 2.30 2.48 (1H, m),2.61-2.67 (2H, m), 2.78-3.02 (2H, m), 4.59-4.73 (1H, m), 4.95 (1H, t,J=3.9 Hz), 5.10 (1H, d, J=3.6 Hz), 6.69-6.87 (3H, m), 7.06 (2H, t, J=8.6Hz), 7.30 (2H, d, J=8.2 Hz), 7.47-7.54 (4H, m); IR (KBr) 3272, 2942,1642, 1514, 1327, 1229, 1165, 1121, 1069, 831 cm⁻¹; Anal. Calcd forC₂₇H₂₄F₅NO₂: C, 66.25; H, 4.94; N, 2.86. Found: C, 66.30; H, 5.18; N,2.66.

Example 325-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]naphthalene-1-carboxamide

1) ethyl 5-nitro-1-naphthoate

A solution of 5-nitro-1-naphthoic acid (see Chem. Pharm. Bull., 32,3968-80 (1984)) (5.995 g, 27.60 mmol) and conc. sulfuric acid (2 ml) inethanol (100 ml) was heated under reflux for one day. The reactionsolution was concentrated, diluted with ethyl acetate, and washed withaqueous sodium hydrogen carbonate solution and water. The obtained ethylacetate solution was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure to give the objectivesubstance.

yellow solid yield 6.212 g, 92%

Recrystallization from ethanol gave a pale-yellow powder. mp 92-93° C.;¹H-NMR (CDCl₃, 200 MHz) δ 1.48 (3H, t, J=7.2 Hz), 4.50 (2H, q, J=7.1Hz), 7.67 (1H, dd, J=7.6 Hz, 8.8 Hz), 7.74 (1H, dd, J=7.2 Hz, 8.8 Hz),8.20 (1H, dd, J=1.1 Hz, 7.7 Hz), 8.29 (1H, dd, J=1.1 Hz, 7.3 Hz), 8.66(1H, td, J=1.0 Hz, 8.8 Hz), 9.26 (1H, td, J=1.0 Hz, 8.6 Hz); IR (KBr)1725, 1520, 1354, 1277, 1155, 793, 764 cm⁻¹; Anal. Calcd for C₁₃H₁₁NO₄:C, 63.67; H, 4.52; N, 5.71. Found: C, 63.45; H, 4.47; N, 5.69.

2) ethyl 5-amino-1-naphthoate

A solution of ethyl 5-nitro-1-naphthoate (3.304 g, 13.47 mmol) inethanol (10 ml)-tetrahydrofuran (20 ml) was hydrogenated under normaltemperature and normal pressure using 10% palladium/carbon (containingwater by 50%) (0.5 g) as a catalyst until the starting materialdisappeared. The catalyst was filtered off and the solvent wasevaporated under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (hexane/ethylacetate=6/1−3/1) to give the objective substance.

yellow liquid yield 2.797 g, 97% ¹H-NMR (CDCl₃, 200 MHz) δ 1.45 (3H, t,J=7.1 Hz), 4.16 (2H, br s), 4.47 (2H, q, J=7.1 Hz), 6.85 (1H, dd, J=0.8Hz, 7.4 Hz), 7.41 (1H, dd, J=7.5 Hz, 8.5 Hz), 7.47 (1H, dd, J=7.2 Hz,8.6 Hz), 8.05 (1H, td, J=1.1 Hz, 8.5 Hz), 8.11 (1H, dd, J=1.2 Hz, 7.2Hz), 8.28 (1H, td, J=0.9 Hz, 8.6 Hz); IR (neat) 3378, 2980, 1705, 1634,1582, 1464, 1260, 1213, 1107, 783 cm⁻¹

3) 5-fluoro-1-naphthoic acid

While stirring ethyl 5-amino-1-naphthoate (1.380 g, 6.411 mmol) andconc. hydrochloric acid (2 ml) in water (15 ml), a solution of sodiumnitrite (0.53 g, 7.69 mmol) in water (1.5 ml) was added dropwise underice-cooling, and the mixture was stirred at said temperature for 10 min.To the reaction solution was added a 60% aqueous hexafluotophosphoricacid solution (1.61 ml, 10.9 mmol) with vigorous stirring underice-cooling and the mixture was stirred as it was for 0.5 hr. Theresulting precipitate was filtered, washed with water andmethanol-diethyl ether (1:4) and dried to give a diazonium salt as abrown powder. The obtained diazonium salt was heated in liquid paraffin(8 ml) at 170° C. for 0.5 hr. The mixture was cooled to room temperatureand aqueous sodium hydrogen carbonate solution was added. The mixturewas extracted twice with ethyl acetate. The collected organic layer wasdried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained crude product was purified bysilica gel column chromatography (hexane/ethyl acetate=15/1) to give amixture of ethyl 5-fluoro-1-naphthoate and liquid paraffin as acolorless liquid. To a solution of obtained liquid in ethanol (30ml)-tetrahydrofuran (30 ml) was added 1N aqueous sodium hydroxidesolution (8 ml, 8 mmol), and the mixture was stirred overnight at roomtemperature. The reaction solution was concentrated, diluted with water,and washed with diethyl ether. The obtained aqueous solution wasacidified with 1N hydrochloric acid and the resulting crystals werefiltered and washed with water and hexane to give the objectivesubstance.

white crystal yield 0.409 g, 34% mp 214-216° C.; ¹H-NMR (DMSO-d₆, 200MHz) δ 7.44 (1H, dd, J=7.8 Hz, 10.4 Hz), 7.60-7.75 (2H, m), 8.25 (1H, d,J=7.0 Hz), 8.32 (1H, d, J=8.8 Hz), 8.70 (1H, d, J=8.4 Hz); IR (KBr)3100-2500, 1678, 1599, 1302, 1246, 1117, 887, 781 cm⁻¹; Anal. Calcd forC₁₁H₇FO₂: C, 69.47; H, 3.71. Found: C, 69.24; H, 3.45.

4)5-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.163 g, 0.520 mmol), 5-fluoro-1-naphthoic acid (0.10 g, 0.52 mmol) and1-hydroxybenzotriazole hydrate (80 mg, 0.52 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10g, 0.52 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white crystal yield 0.216 g, 86% mp 222-224° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) 68 2.93 (1H, dd, J=10.8 Hz, 14.0 Hz), 3.19 (1H, dd, J=3.5 Hz,14.5 Hz), 4.65-4.80 (1H, m), 4.91 (1H, t, J=4.8 Hz), 5.44 (1H, d, J=4.0Hz), 7.02-7.29 (6H, m), 7.38-7.59 (7H, m), 7.90 (1H, d, J=9.4 Hz), 8.08(1H, d, J=8.4 Hz); IR (KBr) 3283, 1642, 1537, 1514, 1327, 1248, 1227,1163, 1121, 1069, 831, 783 cm⁻¹; Anal. Calcd for C₂₇H₂₀F₅NO₂: C, 66.80;H, 4.15; N, 2.89. Found: C, 66.65; H, 4.21; N, 2.68.

Example 33N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.168 g, 0.536 mmol), 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid(see Tetrahedron, 53, 15969-15982 (1990))(94 mg, 0.54 mmol) and1-hydroxybenzotriazole hydrate (82 mg, 0.54 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10g, 0.54 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white crystal yield 0.161 g, 64% mp 219-221° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 1.50-1.73 (4H, m), 2.05-2.35 (2H, m), 2.70 (2H, t, J=6.4 Hz),2.88 (1H, dd, J=10.8 Hz, 14.4 Hz), 3.06 (1H, dd, J=3.8 Hz, 14.0 Hz),4.55-4.70 (1H, m), 4.87 (1H, t, J=4.4 Hz), 5.33 (1H, d, J=3.6 Hz), 6.74(1H, dd, J=2.8 Hz, 5.6 Hz), 6.95-7.09 (4H, m), 7.28-7.37 (3H, m),7.47-7.54 (4H, m); IR (KBr) 3330, 1624, 1534, 1329, 1159, 1123, 1069,831 cm⁻¹; Anal. Calcd for C₂₇H₂₅F₄NO₂: C, 68.78; H, 5.34; N, 2.97.Found: C, 68.62; H, 5.38; N, 2.90.

Example 344-chloro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]naphthalene-1-carboxamide

1) 4-amino-1-naphthoic acid.hydrochloride

4-Amino-1-naphthalenecarbonitrile (9.948 g, 59.14 mmol) and potassiumhydroxide (25 g) were heated under reflux in water (150 ml) for one day.The reaction solution was cooled to room temperature and diluted withwater (150 ml). The insoluble materials were filtered off. The filtratewas acidified with conc. hydrochloric acid and resulting precipitate wascollected by filtration and washed with ethanol and water to give theobjective substance.

brown powder yield 4.67 g, 35% ¹H-NMR (DMSO-d₆, 200 MHz) δ 6.75 (1H, d,J=8.4 Hz), 7.40-7.48 (1H, m), 7.52-7.61 (1H, m), 8.06 (1H, d, J=8.6 Hz),8.16 (1H, d, J=7.6 Hz), 9.10 (1H, d, J=7.8 Hz); IR (KBr) 2838, 1686,1503, 1260, 1204, 1094, 766 cm⁻¹

2) methyl 4-chloro-1-naphthoate

While stirring 4-amino-1-naphthoic acid hydrochloride (2.330 g, 10.42mmol) in conc. hydrochloric acid (20 ml), a solution of sodium nitrite(0.72 g, 10.4 mmol) in water (2 ml) was dropwise added underice-cooling, and the mixture was stirred at said temperature for 0.5 hr.To the reaction solution was added a solution of copper(I) chloride(0.57 g, 5.73 mmol) in conc. hydrochloric acid (4 ml) and conc.hydrochloric acid (50 ml) under ice-cooling and the mixture was stirredat 100° C. for 4 hrs. The mixture was cooled to room temperature, andthe resulting precipitate was collected by filtration, and washed withwater. The obtained precipitate was stirred in a solution (40 ml) of 10%hydrogen chloride in methanol at 70° C. overnight. The solvent of thereaction solution was evaporated under reduced pressure and the obtainedcrude product was purified by silica gel column chromatography(hexane/ethyl acetate=9/1) to give the objective substance.

yellow liquid yield 0.299 g, 13% ¹H-NMR (CDCl₃, 200 MHz) δ 4.00 (3H, s),7.58-7.73 (3H, m), 8.09 (1H, d, J=7.8 Hz), 8.32-8.38 (1H, m), 8.92-9.01(1H, m); IR (neat) 1717, 1508, 1275, 1246, 1194, 1140, 1024, 787, 766cm⁻¹

3) 4-chloro-1-naphthoic acid

To a solution of methyl 4-chloro-1-naphthoate (0.299 g, 1.355 mmol) inmethanol (10 ml)-tetrahydrofuran (5 ml) was added 1N aqueous sodiumhydroxide solution (2.71 ml, 2.71 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was concentrated,diluted with water, acidified with 1N hydrochloric acid and extractedtwice with ethyl acetate. The collected organic layer was dried overanhydrous sodium sulfate and the solvent was evaporated under reducedpressure. The residue was crystallized from diethyl ether-hexane to givethe objective substance.

pale-brown crystal yield 0.234 g, 84% mp 215-217° C.; ¹H-NMR (DMSO-d₆,200 MHz) δ 7.74-7.85 (3H, m), 8.12 (1H, d, J=7.6 Hz), 8.27 8.35 (1H, m),8.91-9.00 (1H, m); IR (KBr) 3100-2500, 1690, 1510, 1283, 1252, 785, 762cm⁻¹; Anal. Calcd for C₁₁H₇ClO₂.0.2H₂O: C, 62.85; H, 3.55. Found: C,62.99; H, 3.31.

4)4-chloro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.155 g, 0.495 mmol), 4-chloro-1-naphthoic acid (0.10 g, 0.49 mmol) and1-hydroxybenzotriazole hydrate (76 mg, 0.49 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (95 mg,0.49 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate, and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white crystal yield 0.173 g, 70% mp 222-223° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.92 (1H, dd, J=10.5 Hz, 14.1 Hz), 3.07 (1H, dd, J=3.1 Hz,14.1 Hz), 4.70-4.85 (1H, m), 5.00 (1H, t, J=3.8 Hz), 5.23 (1H, d, J=3.8Hz), 7.07 (1H, d, J=8.8 Hz), 7.13 (2H, t, J=8.6 Hz), 7.27-7.62 (11H, m),8.24 (1H, d, J=8.4 Hz); IR (KBr) 3274, 1638, 1537, 1514, 1327, 1163,1125, 1069, 833 cm⁻¹; Anal. Calcd for C₂₇H₂₀ClF₄NO₂: C, 64.61; H, 4.02;N, 2.79. Found: C, 64.26; H, 3.88; N, 2.59.

Example 35N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]naphthalene-1-carboxamide

1)(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-olhydrochloride

To a solution of tert-butylN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxyethyl-1-[4-(trifluoromethyl)benzyl]]carbamate(2.58 g, 6.24 mmol) in ethanol (35 ml) was added 20% hydrogen chlorideethanol solution (35 ml) and the mixture was heated under reflux for 30min. The reaction solution was concentrated under reduced pressure, andthe residue was washed with diethyl ether to give the objectivesubstance (2.05 g, 94%) as crystals.

mp 173-174° C.; ¹H-NMR (DMSO-d₆, 200 MHz) δ 2.79. (2H, d, J=6.6 Hz),3.64-3.80 (1H, m), 5.03 (1H, s), 6.30. (1H, d, J=4.0 Hz), 7.10-7.24 (2H,m), 7.33 (2H, d, J=8.0 Hz), 7.38-7.50 (2H, m), 7.59. (2H, d, J=8.0 Hz),8.07 (2H, br s); IR (KBr) 3314, 3009 cm⁻¹; Anal. Calcd forC₁₆H₁₆ClF₄NO.0.5H₂O: C, 53.57; H, 4.78; N, 3.90. Found: C, 53.81; H,4.81; N, 3.74.

2) N-[(1RS,2SR)-2-(4-fluoropheny)-2-hydroxy-1-[4-(trifluoromethyl)phenvl]ethyl]naphthalene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)benzyl]propan-1-olhydrochloride (780 mg, 1.89 mmol) in ethyl acetate (5 ml) were added1-naphthoyl chloride (0.43 ml, 2.84 mmol) and saturated aqueous sodiumhydrogen carbonate (5 ml) and the mixture was stirred for 30 min. Thereaction solution was diluted with water and extracted with ethylacetate. The extract was washed with saturated brine, dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (ethylacetate/hexane=1/2) and recrystallized from ethyl acetate-hexane to givethe objective substance (354 mg, 40%) as crystals.

mp 214-216° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 2.89 (1H, dd, J=11.0 Hz, 14.0Hz), 3.09 (1H, dd, J=4.6 Hz, 13.6 Hz), 3.28 (1H, br s), 4.74-4.91 (1H,m), 5.12 (1H, br s), 5.94 (1H, br d, J=9.4 Hz), 7.05-7.24 (2H, m),7.30-7.66 (1H, m), 7.84 (2H, t, J=9.3 Hz); IR (KBr) 3366, 3285, 1636cm⁻¹; Anal. Calcd for C₂₇H₂₁F₄NO₂: C, 69.37; H, 4.53; N, 3.00. Found: C,69.17; H, 4.56; N, 2.88.

Example 36N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-methyl-1-naphthalenecarboxamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in acetonitrile (30 ml) were added4-methyl-1-naphthalenecarboxylic acid (268 mg, 1.44 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (413 mg,2.15 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:acetone=1:1) andrecrystallized from ethyl acetate-hexane to give the title compound (487mg, 70%).

mp 198-199° C. IR ν max^(KBr)cm⁻¹: 1636, 1620, 1607. Anal. Calcd forC₂₈H₂₃F₄NO₂: C, 69.85; H, 4.81; N, 2.91. Found: C, 69.80; H, 4.92; N,2.79. ¹H-NMR (CDCl₃)δ: 2.58 (3H, s), 2.66-3.06 (1H, m), 3.33 (1H, brs),4.60-4.80 (1H, m), 4.98-5.06 (1H, m), 5.80 (1H, d, J=8.2 Hz), 6.92-7.54(12H, m), 7.59 (1H, d, J=8.6 Hz), 7.89 (1H, d, J=8.2 Hz).

Example 375-chloro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]naphthalene-1-carboxamide

1) ethyl 5-chloro-1-naphthoate

While stirring ethyl 5-amino-1-naphthoate (1.358 g, 6.309 mmol) in conc.hydrochloric acid (10 ml), a solution of sodium nitrite (0.52 g, 7.57mmol) in water (1 ml) was added dropwise under ice-cooling and themixture was stirred at said temperature for 0.5 hr. To the reactionsolution was added a solution of copper(I) chloride (0.34 g, 3.47 mmol)in conc. hydrochloric acid (2 ml) under ice-cooling, and the mixture.was stirred at 100° C. for 0.5 hr. After cooling to room temperature,the reaction solution was diluted with water and extracted twice withethyl acetate. The collected organic layer was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=15/1) to give the objectivesubstance.

colorless liquid yield 0.713 g, 48% ¹H-NMR (CDCl₃, 200 MHz) δ 1.47 (3H,t, J=7.2 Hz), 4.48 (2H, q, J=7.3 Hz), 7.47-7.66 (3H, m), 8.22 (1H, dd,J=1.1 Hz, 7.3 Hz), 8.53 (1H, d, J=8.6 Hz), 8.85 (1H, d, J=8.4 Hz); IR(neat) 1717, 1262, 1196, 1142, 789 cm⁻¹

2) 5-chloro-1-naphthoic acid

To a solution of ethyl 5-chloro-1-naphthoate (0.713 g, 3.038 mmol) inmethanol (20 ml)-tetrahydrofuran (10 ml) was added 1N aqueous sodiumhydroxide solution (4.56 ml, 4.56 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was concentrated,diluted with water and acidified with 1N hydrochloric acid. Theresulting precipitate was collected by filtration, washed with water andhexane to give the objective substance.

white crystal yield 0.547 g, 87% mp 248-250° C.; ¹H-NMR (DMSO-d₆, 200MHz) δ 7.64 (1H, t, J=8.0 Hz), 7.74-7.83 (2H, m), 8.23 (1H, d, J=6.6Hz), 8.46 (1H, d, J=8.6 Hz), 8.84 (1H, d, J=8.8 Hz); IR (KBr) 3100-2550,1678, 1302, 783 cm⁻¹; Anal. Calcd for C₁₁H₇ClO₂: C, 63.94; H, 3.41.Found: C, 63.96; H, 3.60.

3)5-chloro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.163 g, 0.520 mmol), 5-chloro-1-naphthoic acid (0.11 g, 0.52 mmol) and1-hydroxybenzotriazole hydrate (80 mg, 0.52 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10g, 0.52 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white crystal yield 0.223 g, 85% mp 211-212° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.92 (1H, dd, J=10.8 Hz, 14.0 Hz), 3.14 (1H, dd, J=2.7 Hz,13.7 Hz), 4.68-4.83 (1H, m), 4.94 (1H, t, J=4.5 Hz), 5.36 (1H, d, J=3.6Hz), 7.08 (2H, t, J=8.8 Hz), 7.17-7.58 (11H, m), 7.75 (1H, d, J=10.0Hz), 8.27 (1H, d, J=8.4 Hz); IR (KBr) 3277, 1636, 1537, 1514, 1327,1229, 1169, 1121, 1069, 1020, 833, 785 cm⁻¹; Anal. Calcd forC₂₇H₂₀ClF₄NO₂: C, 64.61; H, 4.02; N, 2.79. Found: C, 64.47; H, 4.00; N,2.58.

Example 38N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-4-nitro-5,6,7,8-tetrahydronaphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.139 g, 0.444 mmol),4-nitro-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid (see Chem.Pharm. Bull., 32, 3968-80 (1984))(98 mg, 0.44 mmol) and1-hydroxybenzotriazole hydrate (68 mg, 0.44 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (85 mg,0.44 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-duisopropyl ether-hexane to give theobjective substance.

white crystal yield 0.146 g, 64% mp 207-209° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 1.51-1.75 (4H, m), 2.00-2.15 (1H, m), 2.28 2.43 (1H, m),2.80-3.07 (4H, m), 4.62-4.76 (1H, m), 4.93 (H, t, J=4.2 Hz), 5.11 (1H,d, J=3.6 Hz), 6.89 (1H, d, J=8.0 Hz), 7.08 (2H, t, J=8.8 Hz), 7.18 (1H,d, J=9.2 Hz), 7.32 (2H, d, J=8.2 Hz), 7.48-7.54 (5H, m); IR (KBr) 3275,2944, 1644, 1526, 1331, 1159, 1127, 1069, 835 cm⁻¹; Anal. Calcd forC₂₇H₂₄F₄N₂O₄: C, 62.79; H, 4.68; N, 5.42. Found: C, 62.53; H, 4.49; N,5.30.

Example 39 6-fluoro-N-[(1RS,2SR)-2(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.234 g, 0.747 mmol), 6-fluoro-1-naphthoic acid (see EP0931547A1) (0.14g, 0.75 mmol) and 1-hydroxybenzotriazole hydrate (0.11 g, 0.75 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.14 g, 0.75 mmol) was added, and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solution,dried over anhydrous magnesium sulfate, and passed through silica gel.The solvent was evaporated under reduced pressure and the obtainedresidue was crystallized from ethyl acetate-hexane to give the objectivesubstance.

white crystal yield 0.302 g, 83% mp 223-224° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.85-3.08 (2H, m), 4.73-4.87 (1H, m), 5.04 (1H, s), 5.12 (1H,s), 7.05-7.16 (3H, m), 7.21-7.44 (6H, m), 7.50-7.58 (5H, m), 7.79 (1H,d, J=8.2 Hz); IR (KBr) 3268, 1638, 1516, 1325, 1227, 1167, 1121, 1069,864, 829 cm⁻¹; Anal. Calcd for C₂₇H₂₀F₅NO₂.0.1H₂O: C, 66.56; H, 4.18; N,2.87. Found: C, 66.38; H, 4.28; N, 3.11.

Example 40N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-5-nitronaphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.166 g, 0.530 mmol), 5-nitro-1-naphthoic acid (0.12 g, 0.5.3 mmol) and1-hydroxybenzotriazole hydrate (81 mg, 0.53 mmol) in, acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10g, 0.53 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate, and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white crystal yield 0.258 g, 95% mp 211-214° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.85-3.13 (2H, m), 4.74-4.88 (1H, m), 5.00 (1H, t, J=4.3 Hz),5.19 (1H, d, J=3.6 Hz), 7.10 (2H, t, J=8.6 Hz), 7.34-7.42 (4H; m),7.50-7.70 (7H, m), 8.15 (1H, dd, J=1.1 Hz, 7.7 Hz), 8.49 (1H, d, J=8.4Hz); IR (KBr) 3287, 1680, 1526, 1329, 1115 cm⁻¹; Anal. Calcd forC₂₇H₂₀F₄N₂O₄.DMF: C, 61.54; H, 4.65; N, 7.18. Found: C, 61.24; H, 4.62;N, 7.17.

Example 41N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide

1) 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid

Diethyl 3,4-dihydronaphthalene-1,1 (2H)-dicarboxylate (see J. Org.Chem., 54, 2713-18 (1989)) (5.129 g, 18.56 mmol), sodium chloride (2.17g, 37.1 mmol) and water (1 ml) were heated in dimethyl sulfoxide (10 ml)at 180° C. for 1.5 days. After cooling to room temperature, water wasadded, and the mixture was extracted twice with ethyl acetate. Thecollected organic layer was dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the obtained residuewas purified by silica gel column chromatography (hexane/ethylacetate=15/1) to give a crude product of ethyl1,2,3,4-tetrahydronaphthalene-1-carboxylate as a yellow liquid. To asolution of the obtained liquid in methanol (20 ml)-tetrahydrofuran (10ml) was added 1N aqueous sodium hydroxide solution (30 ml, 30 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was concentrated, diluted with water, and washed with diethylether. The obtained aqueous solution was acidified with 1N hydrochloricacid and extracted twice with diethyl ether. The collected organic layerwas dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure and the obtained residue was crystallized fromdiethyl ether-hexane to give the objective substance.

white crystal yield 0.350 g, 11% mp 80-82° C.; ¹H-NMR (CDCl₃, 200 MHz) δ1.67-2.27 (4H, m), 2.67-2.93 (2H, m), 3.85 (1H, t, J=5.5 Hz), 7.08-7.26(4H, m); IR (KBr) 3065-2500, 1692, 1298, 1225, 951, 752 cm⁻¹; Anal.Calcd for C₁₁H₁₂O₂: C, 74.98; H, 6.86. Found: C, 74.58; H, 7.05.

2)N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluordphenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.295 g, 0.942 mmol), 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid(0.17 g, 0.94 mmol) and 1-hydroxybenzotriazole hydrate (0.14 g, 0.94mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.18 g,0.94 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate, and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white crystal yield 0.359 g, 81% mp 205-214° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 1.35-1.95 (4H, m), 2.59-2.87 (4H, m), 3.45 (1H, t, J=6.1 Hz),4.38-4.49 (1H, m), 4.73 (0.5H, t, J=4.4 Hz), 4.82 (0.5H, t, J=4.1 Hz),5.28 (1H, d, J=4.0 Hz), 6.32 (0.5H, d, J=8.8 Hz), 6.40 (0.5H, d, J=8.4Hz), 6.56 (1H, d, J=7.4 Hz), 6.91-7.23 (7H, m), 7.34-7.50 (4H, m); IR(KBr) 3279, 1647, 1514, 1329, 1167, 1113, 1069 cm⁻¹; Anal. Calcd forC₂₇H₂₅F₄NO₂: C, 68.78; H, 5.34; N, 2.97. Found: C, 68.62; H, 5.24; N,2.90.

Example 42N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-1-carboxamide

1) 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-1-carboxylic acid

To a solution of 6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-1-ylmethanol(see Tetrahedron, 53, 15969-15982 (1990)) (1.232 g, 6.990 mmol) inacetone (50 ml) was slowly added dropwise a solution of chromicanhydride (2.10 g, 21.0 mmol) and conc. sulfuric acid (2 ml) dissolvedin water (9 ml) under ice-cooling. After the completion of the dropwise.addition, the mixture was stirred at room temperature for 2 hrs. Thereaction solution was again ice-cooled, isopropanol (5 ml) was added,and the mixture was stirred as it was for 0.5 hr. The reaction solutionwas diluted with ethyl acetate, washed three times with water and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the obtained residue was crystallized fromethanol-water to give the objective substance.

white crystal yield 0.916 g, 69% mp 111-112° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.60-1.90 (6H, m), 2.88 (2H, t, J=5.5 Hz), 3.17 (2H, t, J=5.1 Hz),7.14 (1H, t, J=7.5 Hz), 7.28 (1H, d, J=7.8 Hz), 7.69 (1H, dd, J=1.5 Hz,7.7 Hz); IR (KBr) 3200-2500, 1690, 1437, 1408, 1283, 1273, 916, 758cm⁻¹; Anal. Calcd for C₁₂H₁₄O₂: C, 75.76; H, 7.42. Found: C, 75.71; H,7.21.

2)N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.163 g, 0.520 mmol),6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-1-carboxylic acid (99 mg,0.52 mmol) and 1-hydroxybenzotriazole hydrate (80 mg, 0.52 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.10 g, 0.52 mmol) was added, and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solution,dried over anhydrous magnesium sulfate and passed through silica gel.The solvent was evaporated under reduced pressure and the obtainedresidue was crystallized from ethyl acetate-hexane to give the objectivesubstance. white crystal yield 0.156 g, 62%

mp 210-211° C.; ¹H-NMR (CDCl₃-DMSO-d₆, 200 MHz) δ 1.35-1.48 (2H, m),1.51-1.61 (2H, m), 1.68 1.81 (2H, m), 2.39-2.47 (2H, m), 2.69-2.80 (2H,m), 2.85-3.02 (2H, m), 4.63-4.77 (1H, m), 4.86 (1H, d, J=3.8 Hz), 4.98(1H, t, J=3.6 Hz), 6.67 (1H, d, J=9.0 Hz), 6.76 (1H, dd, J=1.4 Hz, 7.4Hz), 6.94 7.11 (4H, m), 7.30 (2H, d, J=8.0 Hz), 7.46-7.53 (4H, m); IR(KBr) 3335, 2922, 1622, 1532, 1508, 2327, 1171, 1127, 831 cm⁻¹; Anal.Calcd for C₂₈H₂₇F₄NO₂: C, 69.27; H, 5.61; N, 2.88. Found: C, 69.20; H,5.62; N, 2.86.

Example 434-bromo-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]naphthalene-1-carboxamide

1) (4-bromo-1-naphthyl)methyl acetate

A solution of 1-bromo-4-methylnaphthaleneacetate (14.98 g, 67.75 mmol),N-bromosuccinimide (12.1 g, 67.8 mmol) and 2,2′-azobis(isobutyronitrile)(50 mg) in carbon tetrachloride (50 ml) was heated under reflux for 0.5hr. After cooling the reaction solution to room temperature, whiteprecipitate was filtered off, and the precipitate was washed withdiethyl ether. The solvent of the collected filtrate was evaporatedunder reduced pressure to give a crude product of1-bromo-4-(bromomethyl)naphthalene as a pale-yellow liquid. The obtainedliquid was dissolved in N,N-dimethylformamide (30 ml), sodium acetate(11.1 g, 136 mmol) was added and the mixture was stirred at 60° C. for 6hrs. After cooling to room temperature, the reaction solution wasdiluted with water and extracted twice with ethyl acetate. The collectedorganic layer was dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (hexane/ethylacetate=20/1-6/1) to give the objective substance.

yellow liquid yield 14.97 g, 79% ¹H-NMR (CDCl₃, 200 MHz) δ 2.11 (3H, s),5.53 (2H, s), 7.40 (1H, d, J=7.8 Hz), 7.58-7.69 (2H, m), 7.77 (1H, d,J=7.4 Hz), 7.97-8.05 (1H, m), 8.28-8.36 (1H, m); IR (neat) 1740, 1381,1366, 1225, 1024, 824, 758 cm⁻¹

2) (4-bromo-1-naphthyl)methanol

(4-Bromo-1-naphthyl)methyl acetate (14.97 g, 53.63 mmol) and sodiumhydroxide (3.22 g, 80.4 mmol) were stirred in methanol (50 ml)-water (30ml)-tetrahydrofuran (30 ml) at room temperature for 30 min. The reactionsolution was concentrated, diluted with water, and extracted twice withethyl acetate. The collected organic layer was dried over anhydroussodium sulfate and the solvent was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-2/1) and crystallized fromethyl acetate-hexane to give the objective substance.

white crystal yield 11.77 g, 93% mp 92-93° C.; ¹H-NMR (CDCl₃, 200 MHz) δ1.80 (1H, t, J=5.9 Hz), 5.13 (2H, d, J=5.8 Hz), 7.38 (1H, d, J=7.6 Hz),7.56-7.68 (2H, m), 7.76 (1H, d, J=7.6 Hz), 8.07-8.15 (1H, m), 8.27-8.35(1H, m); IR (KBr) 3214, 1375, 1258, 1073, 997, 822, 748 cm⁻¹; Anal.Calcd for C₁₁H₉BrO: C, 55.72; H, 3.83. Found: C, 55.86; H, 3.70.

3) 4-bromo-1-naphthoic acid

To a solution of (4-bromo-1-naphthyl)methanol (1.329 g, 6.027 mmol) inacetone (50 ml) was added dropwise slowly a solution of chromicanhydride (1.81 g, 18.1 mmol) and conc. sulfuric acid (2 ml) dissolvedin water (9 ml) under ice-cooling. After the completion of the dropwiseaddition, the mixture was stirred at room temperature for 2 hrs. Acetoneof the reaction solution was evaporated under reduced pressure. Theresidue was diluted with ethyl acetate, washed three times with water,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure and the obtained residue was crystallized fromethanol-water to give the objective substance.

pale-brown crystal yield 1.272 g, 84% mp 223-224° C.; ¹H-NMR(CDCl₃-DMSO-d₆, 200 MHz). δ 7.60-7.69 (2H, m), 7.83 (1H, d, J=7.8 Hz),8.06 (1H, d, J=8.2 Hz), 8.28-8.36 (1H, m), 8.99-9.08 (1H, m); IR (KBr)3100-2500, 1694, 1566, 1508, 1279, 1252, 1190, 903, 785, 762 cm⁻¹; Anal.Calcd for C₁₁H₇BrO₂: C, 52.62; H, 2.81. Found: C, 52.42; H, 2.87.

4)4-bromo-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.209 g; 0.667 mmol), 4-bromo-1-naphthoic acid (0.17 g, 0.67 mmol) and1-hydroxybenzotriazole hydrate (0.10 g, 0.67 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.13g, 0.67 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white crystal yield 0.309 g, 85% mp 229-231° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.84-3.11 (2H, m), 4.71-4.85 (1H, m), 5.00 (1H, t, J=4.0 Hz),5.24 (1H, d, J=3.8 Hz), 7.04-7.13 (3H, m), 7.33-7.60 (10H, m), 7.69 (1H,d, J=7.4 Hz), 8.20 (1H, d, J=8.8 Hz); IR (KBr) 3262, 1638, 1537, 1514,1329, 1163, 1125, 1069, 833, 754 cm⁻¹; Anal. Calcd for C₂₇H₂₀BrF₄NO₂: C,59.36; H, 3.69; N, 2.56. Found: C, 59.31; H, 3.84; N, 2.72.

Example 442-cyclopentyl-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]acetamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.156 g, 0.498 mmol), cyclopentylacetic acid (64 mg, 0.50 mmol) and1-hydroxybenzotriazole hydrate (76 mg, 0.50 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (95 mg,0.50 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from hexane to give the objective substance.

white crystal yield 0.185 g, 88% mp 195-196° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 0.75-1.05 (2H, m), 1.25-1.65 (6H, m), 1.92 2.12 (3H, m),2.77-2.81 (2H, m), 4.39-4.52 (1H, m), 4.65 (1H, d, J=3.4 Hz), 4.93 (1H,t, J=3.3 Hz), 6.10 (1H, br d, J=8.4 Hz), 7.06 (2H, t, J=8.8 Hz), 7.21(2H, d, J=8.0 Hz), 7.39-7.49 (4H, m); IR (KBr) 3301, 2949, 1645, 1539,1514, 1327, 1163, 1125, 1069, 829 cm⁻¹; Anal. Calcd for C₂₃H₂₅F₄NO₂: C,65.24; H, 5.95; N, 3.31. Found: C, 65.08; H, 5.90; N, 3.41.

Example 453-cyclopentyl-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]propionamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.157 g, 0.501 mmol), 3-cyclopentylpropionic acid (71 mg, 0.50 mmol)and 1-hydroxybenzotriazole hydrate (77 mg, 0.50. mmol) in acetonitrile(10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96mg, 0.50 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from hexane to give the objective substance.

white crystal yield. 0.180 g, 82% mp 169-170° C.; ¹H-NMR (CDCl₃, 200MHz) δ 0.98 (2H, br s), 1.35-1.70 (9H, m), 2.07 (2H, dt, J=2.6 Hz, 7.4Hz), 2.76 (1H, dd, J=10.4 Hz, 14.4 Hz), 2.90 (1H, dd, J=4.4 Hz, 14.6Hz), 3.61 (1H, d, J=3.6 Hz), 4.36-4.50 (1H, m), 4.97 (1H, t, J=3.5 Hz),5.39 (1H, br d, J=7.8 Hz), 7.08 (2H, t, J=8.8 Hz), 7.21 (2H, d, J=7.8Hz), 7.39 (2H, dd, J=5.6 Hz, 8.4 Hz), 7.51 (2H, d, J=8.0 Hz); IR (KBr)3303, 2951, 1645, 1537, 1514, 1327, 1163, 1123, 1069, 829 cm⁻¹; Anal.Calcd for C₂₄H₂₇F₄NO₂: C, 65.89; H, 6.22; N, 3.20. Found: C, 65.61; H,6.16; N, 3.32.

Example 46N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-1-benzothiophene-3-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.173 g, 0.552 mmol), 1-benzothiophene-3-carboxylic acid (see Synth.Commun., 15, 711-713 (1984)) (0.10 g, 0.55 mmol) and1-hydroxybenzotriazole hydrate (85 mg, 0.55 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11g, 0.55 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from diethyl ether-hexane to give the objective substance.

white crystal yield 0.204 g, 78% mp 188-189° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.88-3.08 (2H, m), 3.64 (1H, d, J=3.6 Hz), 4.59-4.72 (1H, m), 5.13(1H, t, J=3.2 Hz), 6.04 (1H, d, J=8.8 Hz), 7.09 (2H, t, J=8.8 Hz),7.31-7.60 (9H, m), 7.82-7.92 (2H, m); IR (KBr) 3333, 1622, 1537, 1510,1331, 1159, 1123, 1069, 833, 766 cm⁻¹; Anal. Calcd for C₂₅H₁₉F₄NO₂S: C,63.42; H, 4.04; N, 2.96. Found: C, 63.50; H, 4.10; N, 2.90.

Example 47N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-phenylbutyramide

To a solution of 4-phenylbutyric acid (141 mg, 0.86 mmol) intetrahydrofuran (5 ml) were added oxalyl chloride (0.15 ml, 1.72 mmol)and N,N-dimethylformamide (0.01 ml), and the mixture was stirred at roomtemperature for 30 min. The reaction solution was evaporated underreduced pressure. To a solution of the residue in ethyl acetate (5 ml)were added(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (200 mg, 0.57 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml), and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (50 ml) andextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1-1:1) and recrystallized fromethyl acetate-hexane to give the title compound (179 mg, 68%).

mp 150-151° C. IR ν max^(KBr)cm⁻¹: 1645, 1508. Anal. Calcd forC₂₆H₂₅F₄NO₂: C, 67.96; H, 5.48; N, 3.05. Found: C, 67.91; H, 5.35; N,2.98. ¹H-NMR (CDCl₃)δ: 1.70-1.90 (2H, m), 2.00-2.14 (2H, m), 2.51 (2H,t, J=7.4 Hz), 2.70-2.94 (2H, m), 3.44 (1H, d, J=3.6 Hz), 4.30-4.56 (1H,m), 4.92-5.00 (1H, m), 5.38 (1H, d, J=7.0 Hz), 7.00-7.60 (13H, m).

Example 48N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-3-phenylpropanamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in ethyl acetate (20 ml) were added3-phenylpropionyl chloride (320 ml, 2.15 mmol) and saturated aqueoussodium hydrogen carbonate (20 ml) and the mixture was stirred overnightat room temperature. The reaction solution was diluted with water (100ml), and extracted with ethyl acetate (100 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the title compound (560 mg, 88%).

mp 144-145° C. IR ν max^(KBr)cm⁻¹: 1636, 1541. Anal. Calcd forC₂₅H₂₃F₄NO₂: C, 67.41; H, 5.20; N, 3.14. Found: C, 67.30; H, 5.21; N,3.38. ¹H-NMR (CDCl₃)δ: 2.30-2.44 (2H, m), 2.58-2.94 (4H, m), 3.29 (1H,d, J=4.0 Hz), 4.30-4.48 (1H, m), 4.76-7.86 (1H, m), 5.33 (1H, d, J=8.4Hz), 6.98-7.38 (11H, m), 7.46 (2H, d, J=8.0 Hz).

Example 494,4,4-trifluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-3-methyl-2-butenamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.154 g, 0.492 mmol), 4,4,4-trifluoro-3-methyl-2-butenoic acid (76 mg,0.49 mmol) and 1-hydroxybenzotriazole hydrate (75 mg, 0.49 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (94 mg, 0.49 mmol) was added, and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solution,dried over anhydrous magnesium sulfate and passed through silica gel.The solvent was evaporated under reduced pressure and the obtainedresidue was crystallized from diisopropyl ether-hexane to give theobjective substance.

white crystal yield 0.178 g, 81% mp 182-183° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.04 (3H, s), 2.80-2.84 (2H, m), 4.41-4.54 (1H, m), 4.84 (1H,d, J=3.2 Hz), 4.94 (1H, t, J=3.3 Hz), 6.24-6.26 (1H, m), 7.06 (2H, t,J=8.6 Hz), 7.20 (2H, d, J=7.8 Hz), 7.33 (1H, d, J=8.6 Hz), 7.42-7.49(4H, m); IR (KBr) 3297, 1647, 1541, 1514, 1329, 1167, 1119, 1069, 831cm⁻¹; Anal. Calcd for C₂₁H₁₈F₇NO₂: C, 56.13; H, 4.04; N, 3.12. Found: C,56.02; H, 4.04; N, 2.82.

Example 502,3-dichloro-N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)benzamide

To a solution of(1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were added2,3-dichlorobenzoyl chloride (135 mg, 0.64 mmol) and saturated aqueoussodium hydrogen carbonate (5 ml) and the mixture was stirred overnightat room temperature. The reaction solution was diluted with water (50ml) and extracted with ethyl acetate (50 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=2:1) and recrystallizedfrom ethyl acetate-hexane to give the title compound (161 mg, 77%).

mp 187-188° C. IR ν max^(KBr)cm⁻¹: 1647, 1537, 1514. Anal. Calcd forC₂₃H₁₇Cl₂F₄NO₂: C, 56.81; H, 3.52; N, 2.88. Found: C, 56.82; H, 3.38; N,2.85. ¹H-NMR (CDCl₃)δ: 2.80-3.10 (3H, m), 4.60-4.80 (1H, m), 5.08 (1H,d, J=3.8 Hz), 6.06 (1H, d, J=8.8 Hz), 6.96-7.38 (6H, m), 7.40-7.62 (5H,m).

Example 51N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-6-nitronaphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.178 g, 0.568 mmol), 6-nitro-1-naphthoic acid (see J. Org. Chem., 54,3596-602 (1989)) (0.12 g, 0.57 mmol) and 1-hydroxybenzotriazole hydrate(87 mg, 0.57 mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g,0.57 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.white crystal yield 0.256 g, 88%

mp 206-207° C.; ¹H-NMR (CDCl₃-DMSO-d₆, 200 MHz) δ 2.93 (1H, dd, J=11.0Hz, 13.8 Hz), 3.20 (1H, dd, J=3.1 Hz, 14.1 Hz), 4.67-4.82 (1H, m), 4.93(1H, t, J=4.7 Hz), 5.44 (1H, d, J=4.0 Hz), 7.09 (2H, t, J=8.6 Hz),7.38-7.42 (3H, m), 7.51-7.61 (6H, m), 7.95-8.09 (3H, m), 8.76 (1H, d,J=2.2 Hz); IR (KBr) 3297, 1638, 1535, 1346, 1327, 1113, 1069 cm⁻¹; Anal.Calcd for C₂₇H₂₀F₄N₂O₄: C, 63.28; H, 3.93; N, 5.47. Found: C, 63.11; H,3.80; N, 5.34.

Example 52N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)cyclohexanecarboxamide

To a solution of(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (200 mg, 0.57 mmol) in ethyl acetate (5 ml) were addedcyclohexanecarbonyl chloride (126 mg, 0.86 mmol) and saturated aqueoussodium hydrogen carbonate (5 ml) and the mixture was stirred at roomtemperature for 1 hr. The reaction solution was diluted with water (50ml), and extracted with ethyl acetate (50 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. Recrystallization from ethylacetate-hexane gave the title compound (166 mg, 69%).

mp 203-204° C. IR ν max^(KBr)cm⁻¹: 3275, 1645, 1512. Anal. Calcd forC₂₃H₂₅F₄NO₂: C, 65.24; H, 5.95; N, 3.31. Found: C, 65.14; H, 5.83; N,3.50. ¹H-NMR (CDCl₃)δ: 1.00-1.40 (6H, m), 1.50-1.80 (4H, m), 1.80-2.10(1H, m), 2.72-3.00 (2H, m), 3.73 (1H, d, J=3.6 Hz), 4.32-4.52 (1H, m),4.94-5.00 (1H, m), 5.36 (1H, d, J=8.0 Hz), 7.02-7.16 (2H, m), 7.21 (2H,d, J=8.4 Hz), 7.30-7.44 (2H, m), 7.51 (2H, d, J=8.4 Hz).

Example 53N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-3-oxo-2,3-dihydro-1H-indene-1-carboxamide

To a solution of(1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine(150 mg, 0.42 mmol) in acetonitrile (10 ml) were added3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid (73 mg, 0.42 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (119 mg,0.62 mmol) and 1-hydroxy-1H-benzotriazole (63.6 mg, 0.42 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (50 ml) and extracted with ethyl acetate (50ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=1:1)and recrystallized from ethyl acetate-hexane to give a highly polarisomer (61 mg, 31%) of the title compound.

mp 242-243° C. IR ν max^(KBr)cm⁻¹: 1703, 1649, 1539, 1510. Anal. Calcdfor C₂₆H₂₁F₄NO₃.0.1H₂O: C, 65.99; H, 4.52; N, 2.96. Found: C, 65.70; H,4.41; N, 2.83. ¹H-NMR (CDCl₃)δ: 2.20-2.60 (2H, m), 2.70-3.00 (3H, m),3.86-3.98 (1H, m), 4.40-4.62 (1H, m), 4.92-5.02 (1H, m), 6.46-6.60 (1H,m), 6.60-7.00 (1H, m), 7.00-7.20 (2H, m), 7.20-7.60 (8H, m), 7.70 (1H,d, J=6.2 Hz).

Simultaneously, a less polar isomer (74 mg, 38%) of the title compoundwas obtained.

mp 237-238° C. IR ν max^(KBr)cm⁻¹: 1715, 1651, 1549, 1513. Anal. Calcdfor C₂₆H₂₁F₄NO₃: C, 66.24; H, 4.49; N, 2.97. Found: C, 66.19; H, 4.36;N, 2.90. ¹H-NMR (CDCl₃)δ: 2.64-2.92 (4H, m), 3.92-4.00 (1H, m),4.36-4.52 (1H, m), 4.83 (1H, d, J=4.6 Hz), 6.81 (1H, d, J=7.8 Hz),7.00-7.22 (5H, m), 7.38-7.58 (5H, m), 7.54 (1H, d, J=7.0 Hz)

Example 544-cyano-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]naphthalene-1-carboxamide

1) 4-(methoxycarbonyl)-1-naphthoic acid

While stirring naphthalene-1,4-dicarboxylic acid (25.90 g, 119.8 mmol)in tetrahydrofuran (80 ml)-N,N-dimethylformamide (50 ml),1,8-diazabicyclo[5.4.0]-7-undecene (18.2 g, 120 mmol) was added at roomtemperature and the mixture was stirred as it was for 0.5 hr. To thereaction solution was added iodomethane (51.0 g, 359 mmol) at roomtemperature and the mixture was stirred as it was overnight. Thereaction solution was diluted with aqueous sodium hydrogen carbonatesolution, and washed with ethyl acetate. The obtained aqueous solutionwas acidified with conc. hydrochloric acid and extracted twice withethyl acetate. The collected organic layer was dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe obtained residue was purified by silica gel column chromatography(hexane/ethyl acetate=1/1) and crystallized from ethyl acetate-hexane,to give the objective substance.

pale-brown crystal yield 6.309 g, 23% mp 148-150° C.; ¹H-NMR(CDCl₃-DMSO-d₆, 200 MHz) δ 4.02 (3H, s), 7.59-7.68 (2H, m), 8.09 (1H, d,J=7.4 Hz), 8.14 (1H, d, J=7.4 Hz), 8.75-8.84 (1H, m), 8.88-8.96 (1H, m);IR (KBr) 3100-2635, 1723, 1701, 1291, 1281, 1256, 1206, 1152, 775 cm⁻¹;Anal. Calcd for C₁₃H₁₀O₄: C, 67.82; H, 4.38. Found: C, 67.82; H, 4.28.

2) methyl 4-(aminocarbonyl)-1-naphthoate

To a solution of 4-(methoxycarbonyl)-1-naphthoic acid (2.553 g, 11.09mmol) and N,N-dimethylformamide (2 drops) in tetrahydrofuran (40 ml) wasdropwise added oxalyl chloride (1.93 ml, 22.2 mmol) at room temperatureand the mixture was stirred for 0.5 hr. The solvent of the reactionsolution was evaporated under reduced pressure to give a crude productof acid chloride as a liquid. While stirring 15% aqueous ammonia (1.52g, 22.2 mmol) and sodium hydrogen carbonate (1.86 g, 22.2 mmol) intetrahydrofuran (40 ml) under ice-cooling, the liquid obtained above wasdissolved in tetrahydrofuran (40 ml) and added dropwise, and the mixturewas stirred under ice-cooling for 0.5 hr. and at room temperature for0.5 hr. The reaction solution was poured into aqueous sodium hydrogencarbonate solution and extracted twice with ethyl acetate. The collectedorganic layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The obtained residue wascrystallized from ethyl acetate-diethyl ether-hexane to give theobjective substance.

pale-brown crystal yield 2.418 g, 95% mp 182-184° C.; ¹H-NMR (CDCl₃, 200MHz) δ 4.02 (3H, s), 6.64 (1H, br s), 7.21 (1H, br s), 7.56-7.71 (3H,m), 8.13 (1H, d, J=7.8 Hz), 8.34-8.43 (1H, m), 8.83-8.91 (1H, m); IR(KBr) 3374, 3193, 1719, 1647, 1578, 1279, 1250, 1198, 1127, 783 cm⁻¹;Anal. Calcd for C₁₃H₁₁NO₃: C, 68.11; H, 4.84; N, 6.11. Found: C, 67.77;H, 5.20; N, 5.79.

3) methyl 4-cyano-1-naphthoate

Methyl 4-(aminocarbonyl)-1-naphthoate (1.756 g, 7.660 mmol) and thionylchloride (0.68 ml, 15.3 mmol) were stirred in toluene (30 ml) at 80° C.for 30 min. The reaction solution was poured into aqueous sodiumhydrogen carbonate solution, and extracted twice with ethyl acetate. Thecollected organic layer was dried over anhydrous magnesium sulfate, andthe solvent was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (hexane/ethylacetate=6/1) and crystallized from ethyl acetate-hexane to give theobjective substance. white crystal yield 1.021 g, 63%

mp 109-110° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 4.05 (3H, s), 7.69-7.80 (2H,M), 7.94 (1H, d, J=7.6 Hz), 8.15 (1H, d, J=7.6 Hz), 8.28-8.36 (1H, m),8.86-8.94 (1H, m); IR (KBr) 2332, 1717, 1298, 1256, 766 cm⁻¹; Anal.Calcd for C₁₃H₉NO₂: C, 73.92; H, 4.29; N, 6.63. Found: C, 73.93; H,4.29; N, 6.65.

4) 4-cyano-1-naphthoic acid

To a solution of methyl 4-cyanonaphthoate (0.862 g, 4.081 mmol) inmethanol (20 ml)-tetrahydrofuran (20 ml) was added 1N aqueous sodiumhydroxide solution (8.16 ml, 8.16 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was concentrated,diluted with water, acidified with 1N hydrochloric acid, and extractedtwice with ethyl acetate. The collected organic layer was dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was crystallized from ethyl acetate-hexane to givethe objective substance.

white crystal yield 0.730 g, 91% mp 237-238° C.; ¹H-NMR (DMSO-d₆, 200MHz) δ 7.77-7.91 (2H, m), 8.14-8.27 (3H, m), 8.83-8.92 (1H, m); IR (KBr)3100-2550, 2226, 1698, 1516, 1285, 1264, 1204, 795, 770 cm⁻¹; Anal.Calcd for C₁₂H₇NO₂: C, 73.09; H, 3.58; N, 7.10. Found: C, 72.96; H,3.42; N, 7.07.

5)4-cyano-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.155 g, 0.495 mmol), 4-cyano-1-naphthoic acid (0.10 g, 0.49 mmol) and1-hydroxybenzotriazole hydrate (76 mg, 0.49 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (94 mg,0.49 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl cetate, washedwith aqueous sodium hydrogen carbonate solution, dried over anhydrousmagnesium sulfate and passed through silica gel. The solvent wasevaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white crystal yield 0.204 g, 84% mp 199-201° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.84-2.98 (1H, m), 3.18-3.28 (1H, m), 4.65 4.80 (1H, m), 4.85(1H, t, J=5.3 Hz), 5.53 (1H, d, J=4.0 Hz), 7.09 (2H, t, J=8.8 Hz),7.17-7.26 (2H, m), 7.37-7.44 (3H, m), 7.52-7.58 (4H, m), 7.64-7.72 (1H,m), 7.86 (1H, d, J=7.4 Hz), 8.13-8.22 (2H, m); IR (KBr) 3283, 2228,1642, 1539, 1512, 1327, 1163, 1125, 1111, 1069, 839 cm⁻¹; Anal. Calcdfor C₂₈H₂₀F₄N₂O₂.0.1H₂O: C, 68.04; H, 4.12; N, 5.67. Found: C, 67.8.6;H, 4.19; N, 5.55.

Example 554-fluoro-N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)benzamide

To a solution of(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (200 mg, 0.57 mmol) in ethyl acetate (5 ml) were added4-fluorobenzoyl chloride (136 mg, 0.86 mmol) and saturated aqueoussodium hydrogen carbonate (5 ml) and the mixture was stirred at roomtemperature for 1 hr. The reaction solution was diluted with water (50ml), and extracted with ethyl acetate (50 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. Recrystallization from ethylacetate-hexane gave the title compound (182 mg, 73%).

mp 202-203° C. IR ν max^(KBr)cm⁻¹: 3297, 1640, 1607, 1508. Anal. Calcdfor C₂₃H₁₈F₅NO₂: C, 63.45; H, 4.17; N, 3.22. Found: C, 63.30; H, 4.26;N, 3.28. ¹H-NMR (CDCl₃)δ: 2.80-3.06 (2H, m), 3.43 (1H, d, J=3.8 Hz),4.50-4.70 (1H, m), 5.04-5.14 (1H, m), 6.07 (1H, d, J=9.0 Hz), 7.00-7.20(4H, m), 7.20-7.36 (2H, m), 7.40-7.64 (6H, m).

Example 56N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-6-(methyloxy)-1-naphthalenecarboxamide

To a solution of 6-methoxy-1-naphthalenecarboxylic acid (129 mg, 0.64mmol) in tetrahydrofuran (5 ml) were added oxalyl chloride (0.11 ml,1.28 mmol) and N,N-dimethylformamide (0.01 ml), and the mixture wasstirred at room temperature for 30 min. The reaction solution wasevaporated under reduced pressure. To a solution of the residue in ethylacetate (5 ml) were added(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (50 ml), andextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1) and recrystallized from ethylacetate-hexane to give the title compound (148 mg, 69%).

mp 193-194° C. IR ν max^(KBr)cm⁻¹: 1636, 1512. Anal. Calcd forC₂₈H₂₃F₄NO_(3.)0.1H₂O: C, 67.36; H, 4.68; N, 2.81. Found: C, 67.24; H,4.71; N, 2.81. ¹H-NMR (CDCl₃)δ: 2.80-3.16 (2H, m), 3.37 (1H, brs), 3.91(3H, s), 4.70-4.90 (1H, m), 5.09 (1H, brs), 5.95 (1H, d, J=8.4. Hz),6.98-7.18 (5H, m), 7.20-7.40 (3H, m), 7.40-7.60 (5H, m), 7.75 (1H, d,J=8.0 Hz).

Example 57N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-quinolinecarboxamide

To a solution of 4-quinolinecarboxylic acid (111 mg, 0.64 mmol) intetrahydrofuran (5 ml) were added oxalyl chloride (0.11 ml, 1.72 mmol)and N,N-dimethylformamide (0.01 ml), and the mixture was stirred at roomtemperature for 30 min. The reaction solution was evaporated underreduced pressure. To a solution of the residue in ethyl acetate (5 ml)were added(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (50 ml), andextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate) and recrystallized from ethylacetate-hexane to give the title compound (63 mg, 32%).

mp 227-228° C. IR ν max^(KBr)cm⁻¹: 1644, 1508, 1331. Anal. Calcd forC₂₆H₂₀F₄N₂O₂.0.5H₂O:, C, 65.41; H, 4.43; N, 5.87. Found: C, 65.31; H,4.68; N, 5.61. ¹H-NMR (CDCl₃)δ: 2.76-2.98 (1H, m), 3.00-3.16 (1H, m),4.72-4.92 (1H, m), 5.05 (1H, d, J=4.0 Hz), 6.60-6.80 (1H, m), 7.02-7.20(3H, m), 7.22-7.60 (8H, m), 7.62-7.78 (1H, m), 8.05 (1H, d, J=8.4 Hz),8.82 (1H, brs).

Example 583-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]haphthalene-1-carboxamide

1) ethyl 3-nitro-1-naphthoate

A solution of 3-nitro-1-naphthoic acid (see J. Org. Chem., 54, 3596-602(1989)) (3.020 g, 13.91 mmol) and conc. sulfuric acid (1 ml) in ethanol(50 ml) was heated under reflux for 1 day. The reaction solution wasconcentrated, diluted with ethyl acetate, and washed with aqueous sodiumhydrogen carbonate solution and water. The obtained ethyl acetatesolution was dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the obtained residue wascrystallized from diethyl ether-hexane to give the objective substance.

yellow crystal yield 3.137 g, 92% mp 78-79° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.50 (3H, t, J=7.1 Hz), 4.53 (2H, q, J=7.1 Hz), 7.71 (1H, ddd, J=1.0Hz, 6.8 Hz, 8.2 Hz), 7.83 (1H, ddd, J=1.3 Hz, 6.7 Hz, 8.8 Hz), 8.10 (1H,d, J=8.8 Hz), 8.92 (1H, d, J=2.6 Hz), 8.96 (1H, d, J=2.6 Hz), 9.03 (1H,d, J=8.8 Hz); IR (KBr) 1717, 1603, 1526, 1453, 1339, 1281, 1240, 1190,1155, 1140 1024, 795, 766 cm⁻¹; Anal. Calcd for C₁₃H₁₁NO₄: C, 63.67; H,4.52; N, 5.71. Found: C, 63.64; H, 4.44; N, 5.64.

2) ethyl 3-amino-1-naphthoate

A solution of ethyl 3-nitro-1-naphthoate (5.371 g, 21.90 mmol) inethanol (30 ml) was hydrogenated under normal temperature and normalpressure using 10% palladium/carbon (containing water by 50%) (0.5 g) asa catalyst until the starting material disappeared. The catalyst wasfiltered off and the solvent was evaporated under reduced pressure. Theobtained crude product was purified by silica gel column chromatography(hexane/ethyl acetate=6/1−3/1) to give the objective substance.

orange liquid yield 4.681 g, 99% ¹H-NMR (CDCl₃, 200 MHz) δ 1.45 (3H, t,J=7.1 Hz), 3.89 (2H, br s), 4.46 (2H, q, J=7.1 Hz), 7.15 (1H, d, J=2.2Hz), 7.30-7.45 (2H, m), 7.60-7.66 (2H, m), 8.70 (1H, dd, J=1.6 Hz, 8.2Hz); IR (neat) 3465, 3374, 2980, 1705, 1626, 1236, 1202 cm⁻¹

3) 3-fluoro-1-naphthoic acid

While stirring ethyl 3-amino-1-naphthoate (2.318 g, 10.77 mol) and conc.hydrochloric acid (4 ml) in water (30 ml), a solution of sodium nitrite(0.89 g, 12.9 mmol) in water (2 ml) was added dropwise under ice-coolingand the mixture was stirred at said temperature for 10 min. To thereaction solution was added a 60% aqueous hexafluorophosphoric acidsolution (2.70 ml, 18.3 mmol) with vigorous stirring under ice-coolingand the mixture was stirred as it was for 0.5 hr. The resultingprecipitate was filtered, washed with water and methanol-diethyl ether(1:4) and dried to give a diazonium salt as a brown powder. The obtaineddiazonium salt was heated in liquid paraffin (8 ml) at 170° C. for 0.5hr. After cooling to room temperature, aqueous sodium hydrogen carbonatesolution was added, and the mixture was extracted twice with ethylacetate. The collected organic layer was dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theobtained crude product was purified by silica gel column chromatography(hexane/ethyl acetate=15/1) to give a mixture of ethyl3-fluoro-1-naphthoate and liquid paraffin as a pale-yellow liquid. To asolution of the obtained liquid in ethanol (30 ml)-tetrahydrofuran (40ml) was added 1N aqueous sodium hydroxide solution (10 ml, 10 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was concentrated, diluted with water, acidified with dilutehydrochloric acid, and extracted twice with ethyl acetate. The collectedorganic layer was dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. The residue was crystallized fromethyl acetate-hexane to give the objective substance.

pale-yellow crystal yield 0.629 g, 31% mp 185-187° C.; ¹H-NMR (DMSO-d₆,200 MHz) δ 7.58-7.66 (2H, m), 7.94-8.03 (3H, m), 8.82-8.88 (1H, m); IR(KBr) 3150-2550, 1696, 1682, 1296, 1252, 1221, 750 cm⁻¹; Anal. Calcd forC₁₁H₇FO₂: C, 69.47; H, 3.71. Found: C, 69.57; H, 3.80.

4) 3-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.158 g, 0.504 mmol), 3-fluoro-1-naphthoic acid (0.10 g, 0.50 mmol) and1-hydroxybenzotriazole hydrate (77 mg, 0.50 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10g, 0.50 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white crystal yield 0.199 g, 81% mp 223-225° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.92 (1H, dd, J=11.3 Hz, 14.3 Hz), 3.17, (1H, dd, J=3.3 Hz,13.9 Hz), 4.64-4.80 (1H, m), 4.91 (1H, t, J=4.4 Hz), 5.45 (1H, d, J=4.0Hz), 6.98 (1H, dd, J=2.4 Hz, 8.8 Hz), 7.08 (2H, t, J=8.8 Hz), 7.21-7.60(10H, m), 7.74 (1H, d, J=8.6 Hz), 7.99 (1H, d, J=10.0 Hz); IR (KBr)3277, 1642, 1624, 1537, 1514, 1325, 1231, 1165, 1127, 1069, 831 cm⁻¹;Anal. Calcd for C₂₇H₂₀F₅NO₂: C, 66.80; H, 4.15; N, 2.89. Found: C,66.66; H, 4.21; N, 2.70.

Example 594,4,4-trifluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]butylamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.170 g, 0.543. mmol), 4,4,4-trifluorobutanoic acid (77 mg, 0.54 mmol)and 1-hydroxybenzotriazole hydrate (83 mg, 0.54 mmol) in acetonitrile(10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(0.10 g, 0.54 mmol) was added, and the mixture was stirred overnight atroom temperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white crystal yield 0.210 g, 88% mp 178-179° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.15-2.45 (4H, m), 2.74-2.81 (2H, m), 4.33 4.46 (1H, m), 4.88(1H, d, J=3.2 Hz), 4.92 (1H, t, J=3.3 Hz), 7.05 (2H, t, J=8.8 Hz), 7.07(1H, d, J=8.8 Hz), 7.20 (2H, d, J=8.0 Hz), 7.38-7.47 (4H, m); IR (KBr)3299, 1655, 1557, 1514, 1329, 1229, 1107, 1069, 829 cm⁻¹; Anal. Calcdfor C₂₀H₁₈F₇NO₂: C, 54.93; H, 4.15; N, 3.20. Found: C, 54.96; H, 4.22;N, 2.95.

Example 60N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-(methyloxy)benzamide

To a solution of(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (200 mg, 0.57 mmol) in ethyl acetate (5 ml) were added4-anisoyl chloride (146 mg, 0.86 mmol) and saturated aqueous sodiumhydrogen carbonate (5 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (50 ml), andextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) and recrystallized from ethylacetate-hexane to give the title compound (185 mg, 72%).

mp 192-193° C. IR ν max^(KBr)cm⁻¹: 1624, 1609, 1539, 1507, 1329. Anal.Calcd for C₂₄H₂₁F₄NO₃: C, 64.43; H, 4.73; N, 3.13. Found: C, 64.44; H,4.66; N, 3.09. ¹H-NMR (CDCl₃)δ: 2.86-3.00 (2H, m), 3.84 (3H, s),3.80-3.88 (1H, m), 4.50-4.66 (1H, m), 5.06-5.14 (1H, m), 6.00 (1H, d,J=8.0 Hz), 6.88 (2H, d, J=8.8 Hz), 7.02-7.14 (2H, m), 7.20-7.30 (2H, m),7.36-7.60 (6H, m).

Example 61N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-9-oxo-9H-fluorene-4-carboxamide

To a solution of 9-oxo-9H-fluorene-4-carboxylic acid (144 mg, 0.64 mmol)in tetrahydrofuran (5 ml) were added oxalyl chloride (0.11 ml, 1.72mmol) and N,N-dimethylformamide (0.01 ml), and the mixture was stirredat room temperature for 30 min. The reaction solution was evaporatedunder reduced pressure. To a solution of the residue in ethyl acetate (5ml) were added(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (50 ml), andextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1-1:1) and recrystallized fromethyl acetate-hexane to give the title compound (154 mg, 69%).

mp 231-232° C. IR ν max^(KBr)cm⁻¹: 1725, 1638, 1607. Anal. Calcd forC₃₀H₂₁F₄NO₃: C, 69.36; H, 4.07; N, 2.70. Found: C, 69.13; H, 4.22; N,2.53. ¹H-NMR (CD₃OD)δ: 2.78-2.96 (1H, m), 3.49 (1H, d, J=13.2 Hz),4.70-4.80 (2H, m), 6.72 (1H, d, J=7.4 Hz), 6.89 (1H, d, J=7.8 Hz),7.04-7.32 (5H, m), 7.46-7.66 (8H, m).

Example 623,3-dimethyl-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]butylamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.168 g, 0.536 mmol), 3,3-dimethylbutanoic acid (62 mg, 0.54 mmol) and1-hydroxybenzotriazole hydrate (82 mg, 0.54 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10g, 0.54 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from hexane to give the objective substance.

white crystal yield 0.155 g, 70% mp 140-141° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 0.81 (9H, s), 1.87. (1H, d, J=12.8 Hz), 1.99 (1H, d, J=13.0 Hz), 2.71(1H, dd, J=10.8 Hz, 14.8 Hz), 2.91 (1H, dd, J=4.4 Hz, 15.0 Hz), 3.47(1H, d, J=3.6 Hz), 4.32-4.56 (1H, m), 4.97 (1H, t, J=3.1 Hz), 5.31 (1H,br d, J=8.4 Hz), 7.07 (2H, t, J=8.6 Hz), 7.22 (2H, d, J=8.4 Hz), 7.40(2H, dd, J=5.4 Hz, 8.4 Hz), 7.50 (2H, d, J=8.0 Hz); IR (KBr) 3337, 2963,1626, 1534, 1510, 1333, 1231, 1159, 1127, 1071, 826 cm⁻¹; Anal. Calcdfor C₂₂H₂₅F₄NO₂: C, 64.22; H, 6.12; N, 3.40. Found: C, 64.03; H, 6.20;N, 3.16.

Example 63N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-2-naphthalenecarboxamide

To a solution of(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (200 mg, 0.57 mmol) in ethyl acetate (5 ml) were added2-naphthoyl chloride (164 mg, 0.86 mmol) and saturated aqueous sodiumhydrogen carbonate (5 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (50 ml), andextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) and recrystallized from ethylacetate-hexane to give the title compound (175 mg, 65%).

mp 174-175° C. IR ν max^(KBr)cm⁻¹: 1640, 1537, 1514. Anal. Calcd forC₂₇H₂₁F₄NO₂: C, 69.37; H, 4.53; N, 3.00. Found: C, 69.23; H, 4.49; N,2.92. ¹H-NMR (CDCl₃)δ: 2.96-3.04 (2H, m), 3.70 (1H, d, J=3.6 Hz),4.58-4.76 (1H, m), 5.12-5.20 (1H, m), 6.26 (1H, d, J=8.0 Hz), 7.02-7.16(2H, m), 7.31 (1H, s), 7.40-7.64 (7H, m), 7.80-7.90 (3H, m), 8.04 (1H,s)

Example 644-(difluoromethyl)-N-((1S,2R)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

1) To a solution of 4-methyl-1-naphthalenecarboxylic acid (4.14 g, 22.2mmol) in methanol (50 ml) was added thionyl chloride (3 ml), and themixture was stirred at 60° C. overnight. The reaction solution wasconcentrated, water (100 ml) was added and the mixture was extractedwith ethyl acetate (100 ml×2). The extract was washed successively withsaturated aqueous sodium hydrogen carbonate and saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced ressure togive methyl 4-methyl-1-naphthalenecarboxylate (4.32 g, 97%) as acolorless oil.

IR ν max^(KBr)cm⁻¹: 1715, 1591. ¹H-NMR (CDCl₃)δ: 2.75 (3H, s), 3.99 (3H,s), 7.35 (1H, d, J=7.6 Hz), 7.50-7.68 (2H, m), 8.00-8.14 (2H, m),8.92-9.02 (1H, m).

2) To a solution of methyl 4-methyl-1-naphthalenecarboxylate

(4.23 g, 21.1 mmol) in chloroform (70 ml) were added N-bromosuccinimide(4.1 g, 23.2 mmol) and 2,2′-azobis(isobutyronitrile) (175 mg, 1.05 mmol)and the mixture was heated under reflux for 30 min. The reactionsolution was concentrated, water (100 ml) was added and the mixture wasextracted with ethyl acetate (100 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue-was dissolved inN,N-dimethylformamide (50 ml) and sodium acetate (3.46 g, 42.2 mmol) wasadded. The mixture was stirred at room temperature for 1 hr. and at 60°C. overnight. The reaction solution was concentrated, water (100 ml) wasadded and the mixture was extracted with ethyl acetate (100 ml×2). Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=20:1) to givemethyl 4-((acetyloxy)methyl)-1-naphthalenecarboxylate (4.1 g, 74%).

IR ν max^(KBr)cm⁻¹: 1744, 1717, 1595, 1518. Anal. Calcd for C₁₅H₁₄O₄: C,69.76; H, 5.46. Found: C, 69.63; H, 5.54. ¹H-NMR (CDCl₃)δ: 2.14 (3H, s),4.00 (3H, s), 5.59 (2H, s), 7.52-7.70 (3H, m), 7.98-8.08 (1H, m), 8.12(1H, d, J=7.2 Hz), 8.90-9.00 (1H, m),

3) To a solution of methyl4-((acetyloxy)methyl)-1-naphthalenecarboxylate (3.91 g, 15.1 mmol) inmethanol (20 ml) was added 1N aqueous sodium hydroxide solution (15.1ml, 15.1 mmol), and the mixture was stirred at room temperature for 5min. 1N Hydrochloric acid was added to the reaction solution (20 ml) andthe mixture was extracted with ethyl acetate (50 ml×2). The extract waswashed with saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=1:1) to give methyl4-(hydroxymethyl)-1-naphthalenecarboxylate (2.78 g, 85%).

IR ν max^(KBr)cm⁻¹: 1715. Anal. Calcd for C₁₃H₁₂O₃: C, 72.21; H, 5.59.Found: C, 71.92; H, 5.49. ¹H-NMR (CDCl₃)δ: 3.99 (3H, s), 5.16 (2H, s),7.50-7.68 (3H, m), 8.00-8.16 (2H, m), 8.88-8.96 (1H, m).

4) To a solution of methyl 4-(hydroxymethyl)-1-naphthalenecarboxylate(2.0 g, 9.25 mmol) in chloroform (40 ml) was added manganese dioxide(4.0 g), and the mixture was stirred at room temperature for 2 hrs.Manganese dioxide was filtered from the reaction solution using celiteand the filtrate was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=2:1)and recrystallized from ethyl acetate-hexane to give methyl4-formyl-1-naphthalenecarboxylate (1.41 g, 85%).

mp 95-96° C. IR ν max^(KBr)cm⁻¹: 1723, 1696. Anal. Calcd for C₁₃H₁₀O₃:C, 72.89; H, 4.71. Found: C, 72.81; H, 4.87. ¹H-NMR (CDCl₃)δ: 4.04 (3H,s), 7.60-7.78 (2H, m), 7.98 (1H, d, J=7.2 Hz), 8.17 (1H, d, J=7.2 Hz),8.76-8.82 (1H, m), 9.20-9.28 (1H, m), 10.47 (1H, s).

5) To a solution of methyl 4-formyl-1-naphthalenecarboxylate (800 mg,3.73 mmol) in toluene (15 ml) was added diethylaminosulfur trifluoride(750 ml, 5.1 mmol) and the mixture was stirred overnight at roomtemperature. To the reaction solution was added saturated aqueous sodiumhydrogen carbonate (10 ml) and the mixture was extracted with ethylacetate (50 ml×2). The extract was washed with saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=10:1) to give methyl4-(difluoromethyl)-1-naphthalenecarboxylate (522 mg, 59%).

IR ν max^(KBr)cm⁻¹: 1723. Anal. Calcd for C₁₃H₁₀F₂O₂: C, 66.10; H, 4.27.Found: C, 66.07; H, 4.35. ¹H-NMR (CDCl₃)δ: 4.03 (3H, s), 7.19 (1H, t,J=55.0 Hz), 7.60-7.70 (2H, m), 7.75 (1H, d, J=7.8 Hz), 8.10-8.22 (2H,m), 8.86-8.96 (1H, m).

6) To a solution of methyl 4-(difluoromethyl)-1-naphthalenecarboxylate(450 mg, 1.91 mmol) in methanol (5 ml) was added 2N aqueous sodiumhydroxide solution (1.9 ml, 3.8 mmol), and the mixture was stirredovernight at room temperature. 1N Hydrochloric acid was added to thereaction solution (5 ml) and the mixture was extracted with ethylacetate (20 ml×2). The extract was washed with saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was recrystallized from ethyl acetate-hexane to give4-(difluoromethyl)-1-naphthalenecarboxylic acid (344 mg, 81%).

mp 179-180° C. IR ν max^(KBr)cm⁻¹: 1701. Anal. Calcd for C₁₂H₈F₂O₂: C,64.87; H, 3.63. Found: C, 64.76; H, 3.55. ¹H-NMR (CDCl₃)δ: 7.22 (1H, t,J=54.8 Hz), 7.62-7.70 (2H, m), 7.81 (1H, d, J=7.6 Hz), 8.21 (1H, d,J=6.6 Hz), 8.39 (1H, d, J=7.6 Hz), 9.02-9.18 (1H, m).

7) To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(300 mg, 0.96 mmol) in acetonitrile (30 ml) were added4-(difluoromethyl)-1-naphthalenecarboxylic acid (213 mg, 0.96 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (275 mg,1.44 mmol) and 1-hydroxy-1H-benzotriazole (147 mg, 0.96 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1) and recrystallized from ethyl acetate-hexane to givethe-title compound (410 mg, 83%).

mp 212-213° C. IR ν max^(KBr)cm⁻¹: 1640, 1618, 1513. Anal. Calcd forC₂₈H₂₁F₆NO₂: C, 64.99; H, 4.09; N, 2.71. Found: C, 64.77; H, 4.36; N,2.45. ¹H-NMR (CDCl₃)δ: 2.85 (1H, dd, J=14.6, 11.0 Hz), 3.00-3.16 (2H,m), 4.76-4.92 (1H, m), 5.04-5.12 (1H, m), 6.00 (1H, d, J=9.2 Hz),6.82-7.66 (14H, m), 8.10 (1H, d, J=8.4 Hz).

Example 65N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-((methyloxy)methyl)-1-naphthalenecarboxamide

1) To a solution of methyl 4-(hydroxymethyl)-1-naphthalenecarboxylate(1.0 g, 4.62 mmol) in N,N-dimethylformamide (10 ml) was added methyliodide (1 ml), and sodium hydride (222 mg, 5.55 mmol, 60% in oil) wasfurther added at 0° C., and the mixture was stirred at room temperaturefor 10 min. To the reaction solution was added water (30 ml) and themixture was extracted with ethyl acetate (50 ml×2). The extract waswashed with saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=20:1-10:1) to givemethyl 4-((methyloxy)methyl)-1-naphthalenecarboxylate (898 mg, 84%).

IR ν max^(KBr)cm⁻¹: 1717. Anal. Calcd for C₁₄H₁₄O₃.0.1H₂O: C, 72.46; H,6.16. Found: C, 72.66; H, 6.09. ¹H-NMR (CDCl₃)δ: 3.48 (3H, s), 4.00 (3H,s), 4.94 (2H, s), 7.50-7.68 (3H, m), 8.04-8.18. (2H, m), 8.90-8.98 (1H,m).

2) To a solution of methyl4-((methyloxy)methyl)-1-naphthalenecarboxylate (780 mg, 3.38 mmol) inmethanol (10 ml) was added 1N aqueous sodium hydroxide solution (6.76ml, 6.76 mmol), and the mixture was stirred overnight at roomtemperature. 1N Hydrochloric acid was added to the reaction solution (10ml) and the mixture was extracted with ethyl acetate (50 ml×2). Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to give4-((methyloxy)methyl)-1-naphthalenecarboxylic acid (615 mg, 84%).

mp 133-134° C. IR ν max^(KBr)cm⁻¹: 1694. Anal. Calcd for C₁₃H₁₂O₃: C,72.21; H, 5.59. Found: C, 72.10; H, 5.64. ¹H-NMR (CDCl₃)δ: 3.52 (3H, s),4.99 (2H, s), 7.56-7.70 (3H, m), 8.10-8.18 (1H, m), 8.37 (1H, d, J=7.2Hz), 9.10-9.16 (1H, m).

3) To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(300 mg, 0.96 mmol) in acetonitrile (30 ml) were added4-((methyloxy)methyl)-1-naphthalenecarboxylic acid (207 mg, 0.96 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (275 mg,1.44 mmol) and 1-hydroxy-1H-benzotriazole (147 mg, 0.96 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml), and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1-2:1) and recrystallized from ethyl acetate-hexane to givethe title compound (340 mg, 69%).

mp 170-171° C. IR ν max^(KBr)cm⁻¹: 1638, 1618, 1607, 1510. Anal. Calcdfor C₂₉H₂₅F₄NO₃: C, 68.09; H, 4.93; N, 2.74. Found: C, 67.89; H, 5.05;N, 2.45. ¹H-NMR (CDCl₃)δ: 2.82 (1H, dd, J=14.6, 11.0 Hz), 3.03 (1H, dd,J=14.6, 4.4 Hz), 3.46 (3H, s), 4.68-4.88 (1H, m), 4.85 (2H, s),4.92-5.00 (1H, m), 6.05 (1H, d, J=8.8 Hz), 7.00-7.16 (3H, m), 7.22-7.62(10H, m), 8.01 (1H, d, J=8.4 Hz).

Example 66N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-anthracenecarboxamide

To a solution of 1-anthracenecarboxylic acid (143 mg, 0.64 mmol). intetrahydrofuran (5 ml) were added oxalyl chloride (0.11 ml, 1.72 mmol)and N,N-dimethylformamide (0.01 ml), and the mixture was stirred at roomtemperature for 30 min. The reaction solution was evaporated underreduced pressure. To a solution of the residue in ethyl acetate (5 ml)were added(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (50 ml) andextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1) and recrystallized from ethylacetate-hexane to give the title compound (147 mg, 66%).

mp 227-228° C. IR ν max^(KBr)cm⁻¹: 1638, 1615, 1514, 1323. Anal. Calcdfor C₃₁H₂₃F₄NO₂: C, 71.70; H, 4.50; N, 2.70. Found: C, 71.57; H, 4.41;N, 2.68. ¹H-NMR (CDCl₃)δ: 2.90 (1H, dd, J=13.2, 9.8 Hz), 3.54 (1H, d,J=13.2 Hz), 4.70-4.90 (2H, m), 6.94 (1H, d, J=7.0 Hz), 7.06-7.20 (2H,m), 7.28-7.40 (1H, m), 7.40-7.78 (9H, m), 7.81 (1H, s), 7.92-8.06 (2H,m), 8.41 (1H, s).

Example 67N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluorbmethyl)benzyl]ethyl]-2-methylnaphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.224 g, 0.715 mmol), 2-methyl-1-naphthoic acid (0.13 g, 0.71 mmol) and1-hydroxybenzotriazole hydrate (0.11 g, 0.71 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.14g, 0.71 mmol) was added, and the mixture was stirred at 70° C. for 5hrs. The reaction solution was diluted with ethyl acetate, washed withaqueous sodium hydrogen carbonate solution and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1) and crystallized fromdiethyl ether-hexane to give the objective substance.

white crystal yield 0.233 g, 68% mp 96-98° C.; ¹H-NMR (CDCl₃, 200 MHz) δ2.11 (3H, s), 2.69 (1H, dd, J=11.1 Hz, 14.5 Hz), 2.99 3.08 (2H, m),4.96-5.14 (2H, m), 5.88 (1H, d, J=9.6 Hz), 7.02-7.41 (8H, m), 7.46-7.57(4H, m), 7.68 7.75 (2H, m); IR (KBr) 3241, 3058, 1632, 1510, 1327, 1225,1163, 1123, 1069, 814 cm⁻¹; Anal. Calcd for C₂₈H₂₃F₄NO₂: C, 69.85; H,4.81; N, 2.91. Found: C, 69.64; H, 4.72; N, 2.82.

Example 68N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]benzamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.166 g, 0.530 mmol), benzoic acid (65 mg, 0.53 mmol) and1-hydroxybenzotriazole hydrate (81 mg, 0.53 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10g, 0.53 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.white crystal yield 0.178 g, 81%

mp 193-194° C.; ¹H-NMR (CDCl₃-DMSO-d₆, 200 MHz) δ 2.86 (1H, dd, J=4.2Hz, 14.6 Hz), 2.99 (1H, dd, J=10.5 Hz, 14.1 Hz), 4.56-4.69 (1H, m), 5.06(1H, t, J=2.9 Hz), 5.12 (1H, d, J=3.2 Hz), 7.06 (2H, t, J=8.7 Hz),7.17-7.26 (3H, m), 7.35-7.53 (7H, m), 7.67 (2H, d, J=8.0 Hz); IR (KBr)3303, 1638, 1534, 1325, 1227, 1167, 1125, 1069, 829, 698 cm⁻¹; Anal.Calcd for C₂₃H₁₉F₄NO₂: C, 66.18; H, 4.59; N, 3.36. Found: C, 66.05; H,4.51; N, 3.44.

Example 69N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-2-phenylacetamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in ethyl acetate (20 ml) were added phenylacetylchloride (285 ml, 2.15 mmol) and saturated aqueous sodium hydrogencarbonate (20 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (100 ml), andextracted with ethyl acetate (100 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was recrystallized from ethylacetate-hexane to give the title compound (578 mg, 93%).

mp 173-174° C. IR ν max^(KBr)cm⁻¹: 1651, 1539, 1514. Anal. Calcd forC₂₄H₂₁F₄NO₂: C, 66.82; H, 4.91; N, 3.25. Found: C, 66.63; H, 4.78; N,3.19. ¹H-NMR (CDCl₃)δ: 2.62 (1H, dd, J=14.2, 10.6 Hz), 2.81 (1H, dd,J=14.2, 4.4 Hz), 3.44 (2H, s), 3.50 (1H, d, J=3.6 Hz), 4.28-4.42 (1H,m), 4.84-4.92 (1H, m), 5.25 (1H, d, J=8.2 Hz), 6.90-7.10 (6H, m),7.24-7.36 (5H, m), 7.45 (2H, d, J=7.6 Hz).

Example 70N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-2,2,2-trifluoroacetamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.155 g, 0.495 mmol) and sodium hydrogen carbonate (83 mg, 0.99 mmol)in tetrahydrofuran (10 ml), trifluoroacetic anhydride (0.08 ml, 0.59mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white crystal yield 0.154 g, 76% mp 162-163° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.81-2.97 (2H, m), 4.31-4.48 (1H, m), 4.85 5.00 (2H, m),7.01-7.11 (2H, m), 7.17 (2H, d, J=8.0 Hz), 7.39-7.47 (4H, m), 7.79-7.92(1H, m); IR (KBr) 3301, 1701, 1564, 1514, 1327, 1233, 1182, 1128, 1069,833 cm⁻¹; Anal. Calcd for C₁₈H₁₄F₇NO₂: C, 52.82; H, 3.45; N, 3.42.Found: C, 52.98; H, 3.43; N, 3.25.

Example 71N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-2,2,3,3-tetrafluoropropionamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.153 g, 0.488 mmol), 2,2,3,3-tetrafluoropropionic acid (71 mg, 0.49mmol) and 1-hydroxybenzotriazole hydrate (75 mg, 0.49 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (94 mg, 0.49 mmol) was added, and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solutionand dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure and the obtained crude product was purified bysilica gel column chromatography (hexane/ethyl acetate=1/1) andcrystallized from hexane to give the objective substance.

white crystal yield 90 mg, 42% mp 164-166° C.; ¹H-NMR (CDCl₃, 200 MHz) δ2.66. (1H, br s), 2.79-2.96 (2H, m), 4.41-4.55 (1H, m), 4.97 (1H, d,J=4.0 Hz), 5.94 (1H, tt, J=5.5 Hz, 52.9 Hz), 6.55 (1H, br d, J=9.2 Hz),7.10 (2H, t, J=8.6 Hz), 7.18 (2H, d, J=8.0 Hz), 7.40 (2H, dd, J=5.8 Hz,8.6 Hz), 7.50 (2H, d, J=8.0 Hz); IR (KBr) 3304, 1686, 1329, 1231, 1175,1113, 1069, 829 cm⁻¹

Example 72N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1,3-benzodioxole-5-carboxamide

To a solution of(1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were addedpivaloyl chloride (119 mg, 0.64 mmol) and saturated aqueous sodiumhydrogen carbonate (5 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (50 ml) andextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was recrystallized from ethylacetate-hexane to give the title compound (160 mg, 81%).

mp 180-181° C. IR ν max^(KBr)cm⁻¹: 1640, 1605, 1507, 1485. Anal. Calcdfor C₂₄H₁₉F₄NO₄: C, 62.47; H, 4.15; N, 3.04. Found: C, 62.43; H, 4.06;N, 3.06. ¹H-NMR (CDCl₃)δ: 2.80-3.06 (2H, m), 3.70 (1H, d, J=3.6 Hz),4.50-4.66 (1H, m), 5.02-5.10 (1H, m), 5.90-6.10 (1H, m), 6.02 (2H, s),6.77 (1H, d, J=8.8 Hz), 7.00-7.16 (4H, m), 7.20-7.30 (2H, m), 7.36-7.58(4H, m).

Example 734-(4-fluorophenyl)-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-5-methyl-2-(1-methylethyl)furan-3-carboxamide

1) 1-fluoro-4-(2-nitro-1-propenyl)benzene

A mixture of 4-fluorobenzaldehyde (17.02 g, 137.1 mmol), acetic acid(11.5 g, 192 mmol), methylamine hydrochloride (3.70 g, 54.9 mmol),sodium acetate (4.50 g, 54.9 mmol) and nitroethane (41.2 g, 549 mmol)was stirred at 100° C. for 1.5 hrs. The reaction solution was pouredinto water, and extracted three times with ethyl acetate. The collectedorganic layer was dried over anhydrous sodium sulfate and the solventwas evaporated under reduced pressure. The residue was crystallized fromdiethyl ether-hexane to give the objective substance.

yellow crystal yield 18.40 g, 74% mp 59-61° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.45 (3H, s), 7.16 (2H, d, J=8.6 Hz), 7.44 (2H, dd, J=5.4 Hz, 8.8 Hz),8.06 (1H, s); IR (KBr) 1514, 1318, 1225, 982, 847 cm⁻¹; Anal. Calcd forC₉H₈FNO₂: C, 59.67; H, 4.45; N, 7.73. Found: C, 59.51; H, 4.39; N, 7.80.

2) ethyl4-(4-fluorophenyl)-5-methyl-2-(1-methylethyl)furan-3-carboxylate

To a solution of ethyl isobutyrylacetate (20.06 g, 126.8 mmol) and1-fluoro-4-(2-nitro-1-propenyl)benzene (23.0 g, 127 mmol) in ethanol(100 ml) was added piperidine (12.5 ml, 127 mmol) at room temperature,and the mixture was stirred overnight at room temperature and at 80° C.for 1 hr. The solvent of the reaction solution was evaporatedunder-reduced pressure, water (50 ml) and conc. hydrochloric acid (30ml) were added to the residue, and the mixture was stirred at roomtemperature for 1 hr. The reaction solution was extracted twice withethyl acetate and the collected organic layer was dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography(hexane/ethyl acetate=20/1) to give the objective substance.

pale-yellow solid yield 5.958 g, 16%

Recrystallization from cold methanol gave white crystals.

mp 27-28° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 1.09 (3H, t, J=7.2 Hz), 1.30(6H, d, J=7.4 Hz), 2.18 (3H, s), 3.65-3.79 (1H, m), 4.11 (2H, q, J=7.2Hz), 7.04 (2H, t, J=8.8 Hz), 7.21 (2H, dd, J=5.6 Hz, 8.8 Hz); IR (neat)2974, 1707, 1578, 1510, 1221, 1149, 1059 cm⁻¹; Anal. Calcd forC₁₇H₁₉FO₃: C, 70.33; H, 6.60. Found: C, 70.36; H, 6.53.

3) 4-(4-fluorophenyl)-5-methyl-2-(1-methylethyl)furan-3-carboxylic acid

Ethyl 4-(4-fluorophenyl)-5-methyl-2-(1-methylethyl)furan-3-carboxylate(1.500 g, 5.167 mmol) and sodium hydroxide (1.65 g, 41.3 mmol) werestirred in methanol (15 ml)-water (5 ml) at 70° C. for 8 hrs. Thereaction solution was diluted with water, acidified with dilutehydrochloric acid, and extracted twice with ethyl acetate. The collectedorganic layer was dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. The residue was recrystallizedfrom hexane to give the objective substance.

white crystal yield 0.958 g, 71% mp 176-177° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.28 (6H, d, J=7.0 Hz), 2.17 (3H, s), 3.71-3.84 (1H, m), 7.05 (2H, t,J=8.8 Hz), 7.22 (2H, dd, J=5.4 Hz, 8.8 Hz); IR (KBr) 3050-2500, 1680,1512, 1225, 1074, 845 cm⁻¹; Anal. Calcd for C₁₅H₁₅FO₃: C, 68.69; H,5.76. Found: C, 68.57; H, 5.84.

4)4-(4-fluorophenyl)-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-5-methyl-2-(1-methylethyl)furan-3-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.211 g, 0.673 mmol), 4-(4-fluorophenyl)-5-methyl-2-(1-methylethyl)furan-3-carboxylic acid (0.18 g, 0.67 mmol) and 1-hydroxybenzotriazolehydrate (0.10 g, 0.67 mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.13 g,0.67 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white powder yield 0.288 g, 77% mp 134-136° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.19 (3H, d, J=7.0 Hz), 1.25 (3H, d, J=7.0 Hz), 2.09 (3H, s), 2.38(1H, dd, J=10.5 Hz, 14.9 Hz), 2.71 (1H, dd, J=4.3 Hz, 14.3 Hz),3.51-3.65 (1H, m), 3.76 (1H, d, J=4.4 Hz), 4.40-4.53 (1H, m), 4.80 (1H,t, J=3.3 Hz), 5.19 (1H, d, J=8.0 Hz), 6.90-7.13 (7H, m), 7.23-7.30 (3H,m), 7.45 (2H, d, J=8.0 Hz); IR (KBr) 3347, 2973, 2634, 1620, 1605, 1512,1329, 1223, 1163, 1125, 1069, 839 cm⁻¹; Anal. Calcd for C₃₁H₂₈F₅NO₃: C,66.78; H, 5.06; N, 2.51. Found: C, 66.43; H, 5.20; N, 2.41.

Example 74N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)[1,1′-biphenyl]-3-carboxamide

To a solution of 3-biphenylcarboxylic acid (127 mg, 0.64 mmol) intetrahydrofuran (5 ml) were added oxalyl chloride (0.11 ml, 1.72 mmol)and N,N-dimethylformamide (0.01 ml), and the mixture was stirred at roomtemperature for 30 min. The reaction solution was evaporated underreduced pressure. To a solution of the residue in ethyl acetate (5 ml)were added(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (50 ml) andextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) and recrystallized from ethylacetate-hexane to give the title compound (147 mg, 69%).

mp 165-166° C. IR ν max^(KBr)cm⁻¹: 1641, 1539, 1510. Anal. Calcd forC₂₉H₂₃F₄NO₂: C, 70.58; H, 4.70; N, 2.84. Found: C, 70.32; H, 4.80; N,2.67. ¹H-NMR (CDCl₃)δ: 2.90-3.02 (1H, m), 2.99 (1H, s), 3.64 (1H, d,J=3.6 Hz), 4.50-4.70 (1H, m), 5.08-5.18 (1H, m), 6.14 (1H, d, J=6.4 Hz),7.02-7.18 (2H, m), 7.24-7.34 (2H, m), 7.38-7.58 (11H, m), 7.70-7.76 (2H,m).

Example 754-(dimethylamino)-N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

To a solution of(1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine(150 mg, 0.42 mmol) in acetonitrile (10 ml) were added4-dimethylaminonaphthalenecarboxylic acid (89 mg, 0.42 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (119 mg,0.62 mmol) and 1-hydroxy-1H-benzotriazole (63.6 mg, 0.42 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (50 ml) and extracted with ethyl acetate (50ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=1:1)and recrystallized from ethyl acetate-hexane to give the title compound(149 mg, 70%).

mp 169-170° C. IR ν max^(KBr)cm⁻¹: 1634, 1578, 1510. Anal. Calcd forC₂₉H₂₆F₄N₂O₂: C, 68.23; H, 5.13; N, 5.49. Found: C, 68.09; H, 5.11; N,5.32. ¹H-NMR (CDCl₃)δ: 2.88 (6H, s), 2.76-3.14 (2H, m), 3.71 (1H, d,J=4.0 Hz), 4.66-4.84 (2H, m), 5.04-5.12 (1H, m), 5.90 (1H, d, J=8.4 Hz),6.86 (1H, d, J=7.6 Hz), 7.02-7.18 (3H, m), 7.30-7.60 (8H, m), 7.75 (1H,d, J=8.4 Hz), 8.17 (1H, d, J=8.4 Hz).

Example 763-chloro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]naphthalene-1-carboxamide

1) ethyl 3-chloro-1-naphthoate

While stirring ethyl 3-amino-1-naphthoate (2.317 g, 10.76 mmol) in conc.hydrochloric acid (30 ml), a solution of sodium nitrite (0.89 g, 12.9mmol) in water (2 ml) was added dropwise under ice-cooling and themixture was stirred at said temperature for 0.5 hr. To the reactionsolution under ice-cooling was added a solution of copper(I) chloride(0.53 g, 5.38 mmol) in conc. hydrochloric acid (4 ml) under ice-coolingand the mixture was stirred at 100° C. for 0.5 hr. After cooling to roomtemperature, the reaction-solution was diluted with water, and extractedtwice with ethyl acetate. The collected organic layer was dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure and the obtained crude product was purified by silica gelcolumn chromatography (hexane/ethyl acetate=15/1) to give the objectivesubstance.

colorless liquid yield 1.058 g, 42% ¹H-NMR (CDCl₃, 200 MHz) δ 1.47 (3H,t, J=7.0 Hz), 4.48 (2H, q, J=7.1 Hz), 7.51-7.65 (2H, m), 7.80 (1H, dd,J=2.2 Hz, 7.2 Hz), 7.99 (1H, d, J=2.2 Hz), 8.12 (1H, d, J=2.2 Hz), 8.87(1H, dd, J=2.2 Hz, 7.4 Hz); IR (KBr) 1717, 1279, 1240, 1188, 1142 cm⁻¹

2) 3-chloro-1-naphthoic acid

To a solution of ethyl 3-chloro-1-naphthoate (1.056 g, 4.500 mmol) inmethanol (10 ml)-tetrahydrofuran (10 ml) was added 1N aqueous sodiumhydroxide solution (9.00 ml, 9.00 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was concentrated,diluted with water, acidified with 1N hydrochloric acid, and extractedtwice with ethyl acetate. The collected organic layer was dried overanhydrous sodium sulfate and the solvent was evaporated under reducedpressure. The residue was crystallized from ethyl acetate-hexane to givethe objective substance.

white crystal yield 0.769 g, 83% mp 217-218° C.; ¹H-NMR (DMSO-d₆, 200MHz) δ 7.59-7.72 (2H, m), 7.97-8.07 (2H, m), 8.30 (1H, d, J=2.2 Hz),8.81-8.86 (1H, m); IR (KBr) 3100-2600, 1699, 1285, 1254, 1196, 883, 793,745 cm⁻¹; Anal. Calcd for C₁₁H₇ClO₂: C, 63.94; H, 3.41. Found: C, 64.00;H, 3.44.

3)3-chloro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.153 g, 0.488 mmol), 3-chloro-1-naphthoic acid (0.10 g, 0.49 mmol) and1-hydroxybenzotriazole hydrate (75 mg, 0.49 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (94 mg,0.49 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white crystal yield 0.210 g, 86% mp 220-221° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.91 (1H, dd, J=10.7 Hz, 13.5 Hz), 3.19 (1H, dd, J=2.2Hz,13.2 Hz), 4.62-4.77 (1H, m), 4.89 (1H, t, J=5.0 Hz), 5.50 (1H, d, J=4.4Hz), 7.04-7.13 (3H, m), 7.22-7.34 (2H, m), 7.38-7.59 (7H, m), 7.73 (1H,d, J=8.0 Hz), 7.82 (1H, d, J=2.0 Hz), 8.10 (1H, d, J=10.0 Hz); IR (KBr)3285, 1642, 1541, 1514, 1325, 1163, 1119, 1069, 837 cm⁻¹; Anal. Calcdfor C₂₇H₂₀ClF₄NO₂: C, 64.61; H, 4.02; N, 2.79. Found: C, 64.82; H, 4.17;N, 2.74.

Example 77N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-2,3-dihydro-1-benzofuran-7-carboxamide

To a solution of 2,3-dihydro-1-benzofuran-7-carboxylic acid (106 mg,0.64 mmol) in tetrahydrofuran (5 ml) were added oxalyl chloride (0.11ml, 1.72 mmol) and N,N-dimethylformamide (0.01 ml) and the mixture wasstirred at room temperature for 30 min. The reaction solution wasevaporated under reduced pressure. To a solution of the residue in ethylacetate (5 ml) were added(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (50 ml), andextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was recrystallized from ethylacetate-hexane to give the title compound (160 mg, 81%).

mp 121-122° C. IR ν max^(KBr)cm⁻¹: 1780, 1644, 1537. Anal. Calcd forC₂₅H₂₁F₄NO₃: C, 65.36; H, 4.61; N, 3.05. Found: C, 65.41; H, 4.38; N,2.76. ¹H-NMR (CDCl₃)δ: 2.76-3.00 (2H, m), 3.18-3.30 (2H, m), 4.12 (1H,d, J=3.6 Hz), 4.48-4.76 (4H, m), 5.08 (1H, s) 6.90-7.16 (2H, m),7.20-7.52 (6H, m), 7.60 (1H, d, J=7.6 Hz), 7.85 (1H, d, J=7.6 Hz).

Example 782-bromo-N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)acetamide

To a solution of(1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine(2.0 g, 5.54 mmol) in ethyl acetate (50 ml) were added bromoacetylbromide (723 ml, 8.30 mmol) and saturated aqueous sodium hydrogencarbonate (50 ml) and the mixture was stirred at room temperature for 3hrs. The reaction solution was diluted with water (100 ml) and extractedwith ethyl acetate (200 ml×2). The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1-1:1). Recrystallization fromethyl acetate-hexane gave the title compound (2.0 g, 83%).

mp 151-152° C. IR ν max^(KBr)cm⁻¹: 1659, 1647, 1547. Anal. Calcd forC₁₈H₁₆BrF₄NO₂: C, 49.79; H, 3.71; N, 3.23. Found: C, 49.80; H, 3.41; N,3.03. ¹H-NMR (CDCl₃)δ: 2.72-2.96 (3H, m), 3.74 (2H, dd, J=18.4, 13.6Hz), 4.38-4.52 (1H, m), 4.92-5.00 (1H, m), 6.53 (1H, d, J=8.4 Hz),7.02-7.18 (2H, m), 7.22 (2H, d, J=8.0 Hz), 7.32 7.50 (2H, m), 7.51 (2H,d, J=8.0 Hz).

Example 794-butyl-N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)benzamide

To a solution of 4-n-butylbenzoic acid (153 mg, 0.86 mmol) intetrahydrofuran (5 ml) were added oxalyl chloride (0.15 ml, 1.72 mmol)and N,N-dimethylformamide (0.01 ml), and the mixture was stirred at roomtemperature for 30 min. The reaction solution was evaporated underreduced pressure. To a solution of the residue in ethyl acetate (5 ml)were added(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (200 mg, 0.57 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (50 ml), andextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1-1:1). Recrystallization fromethyl acetate-hexane gave the title compound (172 mg, 64%).

mp 171-172° C. IR ν max^(KBr)cm⁻¹: 1638, 1609, 1537, 1512. Anal. Calcdfor C₂₇H₂₇F₄NO₂: C, 68.49; H, 5.75; N, 2.96. Found: C, 68.46; H, 5.89;N, 2.94. ¹H-NMR (CDCl₃)δ: 0.92 (3H, t, J=7.2 Hz), 1.22-1.44 (2H, m),1.48-1.70 (2H, m), 2.63 (2H, t, J=8.0 Hz), 2.80-3.06 (2H, m), 3.84 (1H,d, J=3.0 Hz), 4.50-4.70 (1H, m), 5.08 (1H, s), 6.12 (1H, d, J=8.2 Hz),7.00-7.36 (6H, m), 7.38-7.58 (6H, m).

Example 80N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-8-quinolinecarboxamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(4.50 mg, 1.44 mmol) in acetonitrile (30 ml) were added8-quinolinecarboxylic acid (249 mg, 1.44 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (413 mg,2.15 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml), and extracted with ethyl acetate (100ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=1:1).Recrystallization from ethyl acetate-hexane gave the title compound (162mg, 24%).

mp 83-84° C. IR ν max^(KBr)cm⁻¹: 1644, 1574, 1549. Anal. Calcd forC₂₆H₂₀F₄N₂O₂.1.0H₂O: C, 64.19; H, 4.56; N, 5.76. Found: C, 64.07; H,4.39; N, 5.61. ¹H-NMR (CDCl₃)δ: 2.99 (2H, d, J=7.4 Hz), 4.52 (1H, d,J=3.6 Hz), 4.70-4.90 (1H, m), 5.12-5.20 (1H, m), 6.96-7.08 (2H, m), 7.31(2H, d, J=8.0 Hz), 7.36-7.54 (5H, m), 7.67 (1H, t, J=7.6 Hz), 7.98 (1H,dd, J=8.0, 1.8 Hz), 8.28 (1H, dd, J=8.0, 1.8 Hz), 8.71 (1H, dd, J=4.0,1.8 Hz), 8.79 (1H, dd, J=7.4, 1.8 Hz), 11.49 (1H, d, J=7.6 Hz).

Example 81N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-(trifluoromethyl)benzamide

To a solution of(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (200 mg, 0.57 mmol) in ethyl acetate (5 ml) were added4-(trifluoromethyl)benzoyl chloride (179 mg, 0.86 mmol) and saturatedaqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred atroom temperature for 1 hr. The reaction solution was diluted with water(50 ml), and extracted with ethyl acetate (50 ml×2). The extract waswashed with saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=2:1). Recrystallizationfrom ethyl acetate-hexane gave the title compound (171 mg, 62%).

mp 228-229° C. IR ν max^(KBr)cm⁻¹: 3285, 1641, 1329. Anal. Calcd forC₂₄H₁₈F₇NO₂: C, 59.39; H, 3.74; N, 2.89. Found: C, 59.30; H, 3.74; N,3.04. ¹H-NMR (CDCl₃)δ: 2.90-3.08 (3H, m), 4.56-4.70 (1H, m), 5.04-5.14(1H, m), 6.06-6.20 (1H, m), 7.00-7.20 (2H, m), 7.20-7.34 (2H, m),7.36-7.56 (4H, m), 7.60-7.70 (4H, m).

Example 82N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-2-(1-naphthalenyl)acetamide

To a solution of 1-naphthaleneacetic acid (160 mg, 0.86 mmol) intetrahydrofuran (5 ml) were added oxalyl chloride (0.15 ml, 1.72 mmol)and N,N-dimethylformamide (0.01 ml), and the mixture was stirred at roomtemperature for 30 min. The reaction solution was evaporated underreduced pressure. To a solution of the residue in ethyl acetate (5 ml)were added(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (200 mg, 0.57 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml) and the mixture was stirred at room temperature for 2hrs. The reaction solution was diluted with water (50 ml), and extractedwith ethyl acetate (50 ml×2). The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1-1:1). Recrystallization fromethyl acetate-hexane gave the title compound (175 mg, 64%).

mp 186-187° C. IR ν max^(KBr)cm⁻¹: 3285, 1657, 1539, 1512, 1120. Anal.Calcd for C₂₈H₂₃F₄NO₂: C, 69.85; H, 4.81; N, 2.91. Found: C, 69.62; H,4.68; N, 2.85. ¹H-NMR (CDCl₃)δ: 2.40 (1H, dd, J=14.2, 10.4 Hz), 2.70(1H, dd, J=14.2, 4.0 Hz), 3.28 (2H, d, J=3.6 Hz), 3.90 (2H, d, J=2.2Hz), 4.24-4.40 (1H, m), 4.70-4.84 (1H, m), 5.15 (1H, d, J=7.8 Hz), 6.78(2H, d, J=8.0 Hz), 6.88-7.00 (2H, m), 7.04-7.20 (3H, m), 7.20-7.34 (2H,m), 7.36-7.60 (3H, m), 7.70-7.94 (3H, m).

Example 832-(ethyloxy)-N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

To a solution of2-(ethyloxy)-N-(2-(4-fluorophenyl)-2-oxo-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-aphthalenecarboxamide(400 mg, 0.79 mmol) in methanol (30 ml) was added manganese (II)chloride (198 mg, 1.57 mmol), and the mixture was stirred at roomtemperature for 30 min. To the reaction solution was added sodiumborohydride (30 mg, 0.79 mmol) under ice-cooling and the mixture wasstirred for 1 hr. The reaction solution was poured into 1N hydrochloricacid (30 ml), and extracted with ethyl acetate (50 ml×2). The extractwas washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethylacetate=2:1-1:1). Recrystallization from ethyl acetate-hexane gave2-(ethyloxy)-N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide.The mother liquor after recrystallization was evaporated under reducedpressure, and the obtained crude crystal was washed with a mixed solventof hexane:ethyl acetate=10:1 to give the title compound (37.2 mg, 9%).

mp 157-158° C. IR ν max^(KBr)cm⁻¹: 1622, 1510, 1300, 1236. Anal. Calcdfor C₂₉H₂₅F₄NO₃: C, 68.09; H, 4.93; N, 2.74. Found: C, 67.96; H, 4.86;N, 2.82. ¹H-NMR (CDCl₃)δ: 1.38 (3H, t, 7.0 Hz), 2.62-3.10 (2H, m), 3.28(1H, d, J=4.0 Hz), 4.06-4.30 (2H; m), 4.88-5.04 (1H, m), 5.10-5.22 (1H,m), 6.03 (1H, d, J=9.6 Hz), 7.00-7.20 (3H, m), 7.20-7.60 (9H, m), 7.77(2H, dd, J=20.0, 8.2 Hz).

Example 84N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-9-anthracenecarboxamide

To a solution of 9-anthracenecarboxylic acid (143 mg, 0.64 mmol) intetrahydrofuran (5 ml) were added oxalyl chloride (0.11 ml, 1.72 mmol)and N,N-dimethylformamide (0.01 ml) and the mixture was stirred at roomtemperature for 30 min. The reaction solution was evaporated underreduced pressure.

To a solution of the residue in ethyl acetate (5 ml) were added(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (50 ml) andextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1) and recrystallized from ethylacetate-hexane to give the title compound (136 mg, 61%).

mp 251-252° C. IR ν max^(KBr)cm⁻¹: 1655, 1514, 1335, 1161, 1111. Anal.Calcd for C₃₁H₂₃F₄NO₂: C, 71.95; H, 4.48; N, 2.71. Found: C, 71.81; H,4.55; N, 2.74. ¹H-NMR (CDCl₃)δ: 2.82 (1H, dd, J=14.2, 11.8 Hz), 3.59(1H, d, J=14.0 Hz), 4.74 (1H, d, J=8.0 Hz), 5.16-5.32 (1H, m), 6.57 (1H,d, J=8.8 Hz), 6.76 (1H, d, J=8.8 Hz), 6.96-7.10 (1H, m), 7.10-7.30 (3H,m), 7.30-7.46 (2H, m), 7.54-7.76 (6H, m), 7.84-8.00 (2H, m), 8.42 (1H,s).

Example 85N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-9-oxo-9H-fluorene-1-carboxamide

To a solution of 9-oxo-9H-fluorene-1-carboxylic acid (144 mg, 0.64 mmol)in tetrahydrofuran (5 ml) were added oxalyl chloride (0.11 ml, 1.72mmol) and N,N-dimethylformamide (0.01 ml), and the mixture was stirredat room temperature for 30 min. The reaction solution was evaporatedunder reduced pressure. To a solution of the residue in ethyl acetate (5ml) were added(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml) and the mixture was, stirred overnight at roomtemperature. The reaction solution was diluted with water (50 ml) andextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was recrystallized from ethylacetate-hexane to give the title compound (137 mg, 61%).

mp 185-186° C. IR ν max^(KBr)cm⁻¹: 1698, 1607, 1574. Anal. Calcd forC₃₀H₂₁F₄NO₃.0.1H₂O: C, 69.12; H, 4.10; N, 2.69. Found: C, 68.98; H,3.91; N, 2.63. ¹H-NMR (CDCl₃)δ: 2.90-3.12 (2H, m), 3.85 (1H, s),4.64-4.80 (1H, m), 5.20 (1H, s), 7.00-7.16 (2H, m), 7.20-7.70 (12H, m),8.12 (1H, dd, J=7.2, 2.0 Hz), 10.16 (1H, d, J=7.6 Hz).

Example 86N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-3,5-bis(trifluoromethyl)benzamide

To a solution of(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were-added3,5-bis(trifluoromethyl)benzoyl chloride (117 ml, 0.64 mmol) andsaturated aqueous sodium hydrogen carbonate (5 ml) and the mixture wasstirred overnight at room temperature. The reaction solution was dilutedwith water (50 ml) and extracted with ethyl acetate (50 ml×2). Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue wasrecrystallized from diisopropyl ether-hexane to give the title compound(73 mg, 31%).

mp 150-151° C. IR ν max^(KBr)cm⁻¹: 1651, 1620, 1543, 1512. Anal. Calcdfor C₂₅H₁₇F₁₀NO₂: C, 54.26; H, 3.10; N, 2.53. Found: C, 54.12; H, 2.95;N, 2.38. ¹H-NMR (CDCl₃)δ: 2.80-3.04 (3H, m), 4.60-4.78 (1H, m), 5.13(1H, s), 6.24 (1H, d, J=8.4 Hz), 7.02-7.20 (2H, m), 7.20-7.32 (2H, m),7.40-7.56 (4H, m), 7.90-8.02 (3H, m).

Example 878-bromo-N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

To a solution of 8-bromo-1-naphthalenecarboxylic acid (161 mg,0.64-mmol) in tetrahydrofuran (5 ml) were added oxalyl chloride (0.11ml, 1.72 mmol) and N,N-dimethylformamide (0.01 ml), and the mixture wasstirred at room temperature for 30 min. The reaction solution wasevaporated under reduced pressure. To a solution of the residue in ethylacetate (5 ml). were added(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.43 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (50 ml) andextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1-1:1). Recrystallization fromethyl acetate-hexane gave the title compound (67 mg, 29%).

mp 191-192° C. IR ν max^(KBr)cm⁻¹: 1653, 1634, 1510. Anal. Calcd forC₂₇H₂₀BrF₄NO₂.0.2H₂O: C, 58.97; H, 3.74; N, 2.55. Found: C, 58.73; H,3.44; N, 2.49. ¹H-NMR (CDCl₃)δ: 2.80-3.02 (2H, m), 4.78 (1H, brs),5.02-5.20 (1H, m), 5.60-5.80 (1H, m), 7.04-7.20 (2H, m), 7.22-7.44 (5H,m), 7.44-7.70 (4H, m), 7.74-7.96 (3H, m).

Example 884-(4-fluorobenzoyl)-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]benzenecarboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.224 g, 0.715 mmol), 4-(4-fluorobenzoyl)benzoic acid (0.17 g, 0.71mmol) and 1-hydroxybenzotriazole hydrate (0.11 g, 0.71 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.14 g, 0.71 mmol) was added and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solution,dried over anhydrous magnesium sulfate and passed through silica gel.The solvent was evaporated under reduced pressure and theobtained-residue was crystallized from ethyl acetate-hexane to give theobjective substance.

white crystal yield 0.321 g, 83% mp 156-157° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.83-3.06 (2H, m), 4.60-4.71 (1H, m), 4.91 (1H, d, J=3.2 Hz),5.08 (1H, t, J=3.1 Hz), 7.08 (2H, t, J=8.6 Hz), 7.14-7.31 (5H, m), 7.45(2H, d, J=7.4 Hz), 7.50 (2H, dd, J=5.6 Hz, 8.8 Hz), 7.77 (4H, s), 7.83(2H, dd, J=5.4 Hz, 9.0 Hz); IR (KBr) 3536, 3303, 1644, 1601, 1541, 1507,1329, 1281, 1225, 1161, 1111, 1069, 864, 849 cm⁻¹; Anal. Calcd forC₃₀H₂₂F₅NO₃.0.2H₂O: C, 66.35; H, 4.16; N, 2.58. Found: C, 66.14; H,4.06; N, 2.57.

Example 894-[(Z)-2-(4-chlorophenyl)ethenyl]-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]benzenecarboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.245 g, 0.782 mmol), (Z)-4-[2-(4-chlorophenyl)ethenyl]benzoic acid(0.20 g, 0.78 mmol) and 1-hydroxybenzotriazole hydrate (0.12 g, 0.78mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g,0.78 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized ethyl acetate-hexane to give the objective substance.

white crystal yield 0.378 g, 87% mp 193-194° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.77-3.03 (2H, m), 4.56-4.69 (1H, m), 4.82 (1H, d, J=3.4 Hz),5.05 (1H, t, J=2.8 Hz), 6.61 (2H, s), 6.95 (1H, d, J=9.0 Hz), 7.06 (2H,t, J=8.6 Hz), 7.14-7.30 (8H, m), 7.42-7.56 (6H, m); IR (KBr) 3260, 1642,1512, 1325, 1165, 1115, 1067, 872, 826 cm⁻¹; Anal. Calcd forC₃₁H₂₄ClF₄NO₂: C, 67.21; H, 4.37; N, 2.53. Found: C, 67.00; H, 4.42; N,2.48.

Example 904-(4-chlorophenoxy)-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]benzenecarboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.235 g, 0.750 mmol), 4-(4-chlorophenoxy)benzoic acid (0.19 g, 0.75mmol) and 1-hydroxybenzotriazole hydrate (0.11 g, 0.75 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.14 g, 0.75 mmol) was added and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solution,dried over anhydrous magnesium sulfate and passed through silica gel.The solvent was evaporated under reduced pressure and the obtainedresidue was crystallized from ethyl acetate-hexane to give the objectivesubstance.

white crystal yield 0.353 g, 87% mp 188-189° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.77-3.03 (2H, m), 4.56-4.69 (1H, m), 4.75 (1H, d, J=3.2 Hz),5.06 (1H, t, J=3.1 Hz), 6.85 (1H, d, J=8.4 Hz), 6.95 (2H, d, J=8.8 Hz),6.97 (2H, d, J=9.2 Hz), 7.07 (2H, t, J=8.8 Hz), 7.23 (2H, d, J=8.0 Hz),7.33 (2H, d, J=9.2 Hz), 7.43-7.51. (4H, m), 7.64 (2H, d, J=9.2 Hz); IR(KBr) 3291, 1636, 1512, 1487, 1329, 1256, 1121, 1069, 837, 828 cm⁻¹;Anal. Calcd for C₂₉H₂₂ClF₄NO₃: C, 64.04; H, 4;08; N, 2.58. Found: C,63.86; H, 4.06; N, 2.55.

Example 914-(4-fluorophenyl)-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-5-[(methoxy)methyl]-2-phenylfuran-3-carboxamide

1) ethyl 4-(4-fluorophenyl)-5-methyl-2-phenylfuran-3-carboxylate

To a solution of ethyl benzoylacetate (12.43 g, 64.67 mmol) and1-fluoro-4-(2-nitro-1-propenyl)benzene (11.7 g, 64.7 mmol) in ethanol(60 ml) was added piperidine (6.40 ml, 64.7 mmol) at room temperature,and the mixture was stirred overnight at room temperature. To thereaction solution were added water (50 ml) and conc. hydrochloric acid(15 ml), and the mixture was stirred at room temperature for 1 hr. Thereaction solution was extracted twice with ethyl acetate, and thecollected organic layer was dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=20/1) to givethe objective substance.

pale-yellow solid yield 7.860 g, 38%

Recrystallization from methanol gave a white powder.

mp 78-79° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 1.02 (3H, t, J=7.1 Hz), 2.30(3H, s), 4.10 (2H, q, J=7.1 Hz), 7.09 (2H, t, J=8.6 Hz), 7.19-7.48 (5H,m), 7.82 (2H, dd, J=1.9 Hz, 7.7 Hz); IR (KBr) 1716, 1510, 1323, 1223,1105 cm⁻¹; Anal. Calcd for C₂₀H₁₇FO₃: C, 74.06; H, 5.28. Found: C,73.82; H, 5.35.

2) ethyl5-[(acetoxy)methyl]-4-(4-fluorophenyl)-2-phenylfuran-3-carboxylate

A solution of ethyl4-(4-fluorophenyl)-5-methyl-2-phenylfuran-3-carboxylate (19.06 g, 58.76mmol), N-bromosuccinimide (10.5 g, 58.8 mmol) and2,2′-azobis(isobutyronitrile) (50 mg) in carbon tetrachloride (50 ml)was heated under reflux for 0.5 hr. After cooling the reaction solutionto room temperature, white precipitate was removed by filtration, andthe precipitate was washed with diethyl ether. The solvent of thecollected filtrate was evaporated under reduced pressure to give a crudeproduct of ethyl5-(bromomethyl)-4-(4-fluorophenyl)-2-phenylfuran-3-carboxylate as ayellow liquid. The obtained liquid was dissolved inN,N-dimethylformamide (40 ml) and sodium acetate (9.64 g, 118 mmol) wasadded. The mixture was stirred overnight at room temperature. Thereaction solution was diluted with water and extracted twice with ethylacetate. The collected organic layer was dried over anhydrous sodiumsulfate and the solvent was evaporated under reduced pressure. Theobtained crude product was purified by silica gel column chromatography(hexane/ethyl acetate=6/1) to give the objective substance.

pale-yellow solid yield 17.24 g, 77%

Recrystallization from diisopropyl ether gave a pale-brown powder.

mp 114-116° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 1.02 (3H, t, J=7.1 Hz), 2.10(3H, s), 4.11 (2H, q, J=7.1 Hz), 5.01 (2H, s), 7.11 (2H, t, J=8.6 Hz),7.33 (2H, dd, J=5.6 Hz, 8.8 Hz), 7.42-7.51 (3H, m), 7.81-7.87 (2H, m);IR (KBr) 1740, 1717, 1508, 1242, 1223, 1130, 1024, 849, 700 cm⁻¹; Anal.Calcd for C₂₂H₁₉FO₅: C, 69.10; H, 5.01. Found: C, 69.08; H, 5.07.

3) ethyl4-(4-fluorophenyl)-5-[(methoxy)methyl]-2-phenylfuran-3-carboxylate

A mixture of ethyl5-[(acetoxy)methyl]-4-(4-fluorophenyl)-2-phenylfuran-3-carboxylate(4.020 g, 10.51 mmol) and a solution (50 ml) of 10% hydrogen chloride inmethanol was stirred at room temperature for 2.5 days. The solvent ofthe reaction solution was evaporated under reduced pressure and theobtained crude product was purified by silica gel column chromatography(hexane/ethyl acetate=9/1) to give the objective substance.

yellow liquid yield 2.130 g, 57% ¹H-NMR (CDCl₃, 200 MHz) δ 1.02 (3H, t,J=7.1 Hz), 3.37 (3H, s), 4.12 (2H, q, J=7.2 Hz), 4.33 (2H, s), 7.10 (2H,t, J=8.8 Hz), 7.36 (2H, dd, J=5.4 Hz, 8.8 Hz), 7.40-7.49 (3H, m),7.81-7.89 (2H, m); IR (neat) 1717, 1508, 1223, 1109, 1096 cm⁻¹

4) 4-(4-fluorophenyl)-5-[(methoxy)methyl]-2-phenylfuran-3-carboxylicacid

Ethyl 4-(4-fluorophenyl)-5-[(methoxy)methyl]-2-phenylfuran-3-carboxylate(1.535 g, 4.332 mmol) and 2N aqueous sodium hydroxide solution (4.33 ml,8.66 mmol) were stirred in methanol (20 ml) at 70° C. for 8 hrs. Thereaction solution was diluted with water, acidified with dilutehydrochloric acid, and extracted twice with ethyl acetate. The collectedorganic layer was dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=3/1-ethylacetate). Crystallization from hexane gave the objective substance.

pale-brown crystal yield 1.006 g, 71% mp 175-176° C.; ¹H-NMR (CDCl₃, 200MHz) δ 3.36 (3H, s), 4.31 (2H, s), 7.08 (2H, t, J=8.8 Hz), 7.35 (2H, dd,J=5.6 Hz, 8.8 Hz), 7.41-7.44 (3H, m), 7.78-7.85 (2H, m); IR (KBr)3055-2555, 1686, 1508, 1225, 1100, 851 cm⁻¹; Anal. Calcd for C₁₉H₁₅FO₄:C, 69.93; H, 4.63. Found: C, 69.76; H, 4.71.

5)4-(4-fluorophenyl)-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-5-[(methoxy)methyl]-2-phenylfuran-3-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.228 g, 0.728 mmol),4-(4-fluorophenyl)-5-[(methoxy)methyl]-2-phenylfuran-3-carboxylic acid(0.24 g, 0.73 mmol) and 1-hydroxybenzotriazole hydrate (0.11 g, 0.73mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.14 g,0.73 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white crystal yield 0.341 g, 75% mp 204-206° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.48 (1H, d, J=4.0 Hz), 2.51-2.70 (2H, m), 3.43 (3H, s), 4.32 (2H, s),4.51-4.64 (1H, m), 4.75 (1H, t, J=3.7 Hz), 5.61 (1H, d, J=8.4 Hz),6.90-7.00 (4H, m), 7.09 (2H, t, J=8.6 Hz), 7.19 (2H, dd, J=5.2 Hz, 8.6Hz), 7.30-7.42 (7H, m), 7.56-7.61 (2H, m); IR (KBr) 3301, 1636, 1512,1329, 1223, 1163, 1123, 1094, 1069, 839 cm⁻¹; Anal. Calcd forC₃₅H₂₈F₅NO₄: C, 67.63; H, 4.54; N, 2.25. Found: C, 67.46; H, 4.71; N,2.25.

Example 924-[2-(4-chlorophenyl)ethyl]-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]benzenecarboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.219 g, 0.699 mmol), 4-[2-(4-chlorophenyl)ethyl]benzoic acid (0.18 g,0.70 mmol) and 1-hydroxybenzotriazole hydrate (0.11 g, 0.70 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.13 g, 0.70 mmol) was added and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solution,dried over anhydrous magnesium sulfate and passed through silica gel.The solvent was evaporated under reduced pressure. The obtained residuewas crystallized from ethyl acetate-hexane to give the objectivesubstance.

white crystal yield 0.345 g, 89% mp 211-212° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.56-3.06 (6H, m), 4.53-4.66 (1H, m), 5.03 (1H, t, J=3.1 Hz),5.32 (1H, d, J=3.6 Hz), 7.01-7.27 (9H, m), 7.36-7.54 (6H, m), 7.60 (2H,d, J=8.2 Hz); IR (KBr) 3287, 1638, 1541, 1512, 1325, 1229, 1163, 1115,1067, 837 cm⁻¹; Anal. Calcd for C₃₁H₂₆ClF₄NO₂: C, 66.97; H, 4.71; N,2.52. Found: C, 66.65; H, 4.62; N, 2.51.

Example 934-[cis-3-(4-chlorophenyl)oxiran-2-yl]-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]benzenecarboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.264 g, 0.843 mmol), cis-4-[3-(4-chlorophenyl)oxiran-2-yl]benzoic acid(0.23 g, 0.84 mmol) and 1-hydroxybenzotriazole hydrate (0.13 g, 0.84mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.16 g,0.84 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solvent,was evaporated under reduced pressure and the obtained residue wascrystallized ethyl acetate-hexane to give the objective substance.

white powder yield 0.288 g, 60% mp 162-166° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.91 (2H, d, J=7.4 Hz), 3.49 (1H, dd, J=3.5 Hz, 10.5 Hz), 4.36 (2H,S), 4.46-4.63 (1H, m), 5.05 (1H, t, J=3.1 Hz), 6.03-6.08 (1H, m),7.02-7.23 (10H, m), 7.36-7.43 (4H, m), 7.47 (2H, d, J=8.0 Hz); IR (KBr)3289, 1642, 1541, 1510, 1325, 1229, 1163, 1111, 1067, 1019, 828 cm⁻¹;Anal. Calcd for C₃₁H₂₄ClF₄NO₃: C, 65.32; H, 4.24; N, 2.46. Found: C,65.21; H, 4.01; N, 2.44.

Example 94N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-4-(2-phenyl-1,3-dithiolan-2-yl)benzenecarboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.218 g, 0.696 mmol), 4-(2-phenyl-1,3-dithiolan-2-yl)benzoic acid (0.21g, 0.70 mmol) and 1-hydroxybenzotriazole hydrate (0.11 g, 0.70 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.13 g, 0.70 mmol) was added and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solution,dried over anhydrous magnesium sulfate and passed through silica gel.The solvent was evaporated under reduced pressure and the obtainedresidue was crystallized from ethyl acetate-hexane to give the objectivesubstance.

white amorphous powder yield 0.363 g, 87% ¹H-NMR (CDCl₃, 200 MHz) δ2.82-2.99 (2H, m), 3.32-3.51 (4H, m), 3.56 (1H, d, J=3.6 Hz), 4.54-4.68(1H, m), 5.06 (1H, t, J=3.1 Hz), 6.12 (1H, d, J=8.4 Hz), 7.08 (2H, t,J=8.6 Hz), 7.22-7.35 (6H, m), 7.38-7.57 (7H, m), 7.64 (2H, d, J=8.4 Hz);IR (KBr) 3241, 1640, 1624, 1541, 1510, 1325, 1223, 1161, 1119, 1067, 829cm⁻¹; Anal. Calcd for C₃₂H₂₇F₄NO₂S₂: C, 64.31; H, 4.55; N, 2.34. Found:C, 64.20; H, 4.44; N, 2.60.

Example 955-(4-fluorophenyl)-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-2-methylfuran-3-carboxamide

1) methyl 5-(4-fluorophenyl)-2-methyl-3-furancarboxylate

To a solution of 1,8-diazabicyclo[5.4.0]-7-undecene (44.2 g, 290 mmol)in toluene (250 ml) was added methyl acetoacetate (33.7 g, 290 mmol) atroom temperature, and 2-chloro-4′-fluoroacetophenone (50.08 g, 290.2mmol) was added thereto. The mixture was stirred at room temperature for1 hr. The obtained toluene solution was washed three times with waterand p-toluenesulfonic acid monohydrate (5 g) was added. The mixture washeated under reflux for 1 hr in a reaction container equipped with aDean-Stark trap under dehydrated conditions. The reaction solution wascooled to room temperature, washed with water, dried over anhydrousmagnesium sulfate and the solvent was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=20/1-9/1). Crystallization fromcold methanol gave the objective substance.

yellow crystal yield 31.26 g, 46% mp 96-97° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.64 (3H, s), 3.85 (3H, s), 6.81 (1H, s), 7.08 (2H, t, J=8.8 Hz), 7.60(2H, dd, J=5.4 Hz, 9.0 Hz); IR (KBr) 1705, 1501, 1449, 1233, 1105, 1044,843, 829, 779 cm⁻¹; Anal. Calcd for C₁₃H₁₁FO₃: C, 66.66; H, 4.73. Found:C, 66.63; H, 4.56.

2) 5-(4-fluorophenyl)-2-methyl-3-furancarboxylic acid

Methyl 5-(4-fluorophenyl)-2-methyl-3-furancarboxylate (15.36 g, 65.58mmol) and sodium hydroxide (5.25 g, 131 mmol) were stirred in methanol(100 ml) and water (50 ml) at room temperature overnight. The reactionsolution was concentrated, diluted with water, acidified with conc.hydrochloric acid and washed three times with ethyl acetate. Thecollected organic layer was dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue wascrystallized from ethyl acetate-hexane to give the objective substance.

pale-yellow crystal yield 13.42 g, 93% mp 217-218° C.; ¹H-NMR(CDCl₃-DMSO-d₆, 200 MHz) δ 2.65 (3H, s), 6.83 (1H, s), 7.07 (2H, t,J=8.6 Hz), 7.60 (2H, dd, J=5.0 Hz, 8.8 Hz); IR (KBr) 3100-2500, 1694,1505, 1474, 1233, 774 cm⁻¹; Anal. Calcd for C₁₂H₉FO₃: C, 65.46; H, 4.12.Found: C, 65.50; H, 4.15.

3)5-(4-fluorophenyl)-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-2-methylfuran-3-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.219 g, 0.699 mmol), 5-(4-fluorophenyl)-2-methyl-3-furancarboxylicacid (0.15 g, 0.70 mmol) and 1-hydroxybenzotriazole hydrate (0.11 g,0.70 mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.13 g,0.70 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white powder yield 0.273 g, 76% mp 179-181° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.52 (3H, s), 2.76-2.99 (2H, m), 3.73 (1H, d, J=3.6 Hz), 4.51-4.66(1H, m), 5.08 (1H, t, J=3.3 Hz), 5.74 (1H, d, J=8.2 Hz), 6.35 (1H, s),7.03-7.15 (4H, m), 7.24 (2H, d, J=8.0 Hz), 7.43 (2H, dd, J=5.4 Hz, 8.8Hz), 7.49-7.58 (4H, m); IR (KBr) 3266, 1640, 1510, 1501, 1327, 1233,1165, 1123, 1069, 837 cm⁻¹

Example 964-[(Z)-2-(2-chlorophenyl)ethenyl]-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]benzenecarboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.208 g, 0.664 mmol), (Z)-4-[2-(2-chlorophenyl)ethenyl]benzoic acid(0.17 g, 0.66 mmol) and 1-hydroxybenzotriazole hydrate (0.10 g, 0.66mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.13 g,0.66 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white powder yield 0.312 g, 85% mp 153-154° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.81-2.97 (2H, m), 3.60 (1H, d, J=3.4 Hz), 4.51-4.64 (1H, m),5.06 (1H, s), 6.09 (1H, d, J=8.4 Hz), 6.68 (1H, d, J=12.2 Hz), 6.78 (1H,d, J=12.4 Hz), 6.99-7.26 (9H, m), 7.36-7.50 (7H, m); IR (KBr) 3291,1638, 1539, 1514, 1325, 1231, 1165, 1119, 1069 cm⁻¹; Anal. Calcd forC₃₁H₂₄ClF₄NO₂: C, 67.21; H, 4.37; N, 2.53. Found: C, 66.90; H, 4.01; N,2.39.

Example 97N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-2-[(phenylthio)methyl]naphthalene-1-carboxamide

1) methyl 2-methyl-1-naphthoate

To a solution of 2-methyl-1-naphthoate (7.579 g, 40.70 mol) andN,N-dimethylformamide (3 drops) in tetrahydrofuran (40 ml) was dropwiseadded oxalyl chloride (7.10 ml, 81.4 mmol) at room temperature and themixture was stirred for 0.5 hr. The solvent of the reaction solution wasevaporated under reduced pressure to give a crude product of the acidchloride as a liquid. To a solution of methanol (2.47 ml, 61.1 mmol),4-N,N-dimethylaminopyridine (0.50 g, 4.07 mmol) and triethylamine (8.51ml, 61.1 mmol) in acetonitrile (50 ml) was dropwise added a solution ofthe liquid obtained above dissolved in acetonitrile (20 ml) underice-cooling, and the mixture was stirred overnight at room temperature.The reaction solution was poured into water and extracted twice withethyl acetate. The collected organic layer was dried over anhydrousmagnesium sulfate and the solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography(hexane/ethyl acetate=6/1) to give the objective substance.

pale-yellow liquid yield 7.866 g, 97% ¹H-NMR (CDCl₃, 200 MHz) δ 2.51(3H, s), 4.04 (3H, s), 7.32 (1H, d, J=8.4 Hz), 7.41-7.55 (2H, m),7.77-7.83 (3H, m); IR (neat) 1728, 1435, 1281, 1244, 1219, 1138, 1051,814 cm⁻¹

2) methyl 2-[(phenylthio)methyl]-1-naphthoate

A solution of methyl 2-methyl-1-naphthoate (1.277 g, 6.377 mmol),N-bromosuccinimide (1.14 g, 6.38 mmol) and 2,2′-azobis(isobutyronitrile)(10 mg) in carbon tetrachloride (10 ml) was heated under reflux for 0.5hr. After cooling the reaction solution to room temperature, the whiteprecipitate was removed by filtration, and the precipitate was washedwith diethyl ether. The solvent of the collected filtrate was evaporatedunder reduced pressure to give a crude product of methyl2-bromomethyl-1-naphthoate as a pale-yellow liquid. The obtained liquid,thiophenol (0.84 g, 7.65 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene(1.14 ml, 7.65 mmol) were stirred in acetonitrile (20 ml) overnight atroom temperature. The solvent of the reaction solution was evaporatedunder reduced pressure, and the obtained crude product was purified bysilica gel column chromatography (hexane/ethyl acetate=20/1-9/1) to givethe objective substance.

yellow liquid yield 1.606 g, 82% ¹H-NMR (CDCl₃, 200 MHz) δ 3.99 (3H, s),4.32 (2H, s), 7.14-7.35 (5H, m), 7.40-7.56 (3H, m), 7.79-7.88 (3H, m);IR (neat) 1723, 1437, 1287, 1252, 1233, 1209, 1140, 1036, 747 cm⁻¹

3) 2-[(phenylthio)methyl]-1-naphthoate

Methyl 2-[(phenylthio)methyl]-1-naphthoate (1.477 g, 4.789 mmol) andsodium hydroxide (2.50 g, 62.5 mmol) were heated under reflux inmethanol (30 ml) and tetrahydrofuran (20 ml) for 6 hrs. The reactionsolution was concentrated, diluted with water, acidified with conc.hydrochloric acid and extracted twice with ethyl acetate. The collectedorganic layer was dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=3/1-1/1).Crystallization from diethyl ether-hexane gave the objective substance.

pale-yellow crystal yield 0.880 g, 62% mp 100-101° C.; ¹H-NMR (CDCl₃,200 MHz) δ 4.47 (2H, s), 7.16-7.58 (8H, m), 7.81-7.87 (2H, m), 8.13-8.18(1H, m); IR (KBr) 3100-2600, 1680, 1283, 1262, 756, 733 cm⁻¹; Anal.Calcd for C₁₈H₁₄O₂S: C, 73.44; H, 4.79. Found: C, 73.17; H, 4.81.

4)N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-2-[(phenylthio)methyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.260 g, 0.830 mmol), 2-[(phenylthio)methyl]-1-naphthoate (0.24 g, 0.83mmol) and 1-hydroxybenzotriazole hydrate (0.13 g, 0.83 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.16 g, 0.83 mmol) was added and the mixture was stirredovernight at 80° C. The reaction solution was diluted with ethylacetate, washed with aqueous sodium hydrogen carbonate solution, driedover anhydrous magnesium sulfate and the solvent was evaporated underreduced pressure. The obtained crude product was purified by silica gelcolumn chromatography (hexane/ethyl acetate=3/1-1/1). Crystallizationfrom ethyl acetate-hexane gave the objective substance.

white powder yield 0.337 g, 69% mp 102-104° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.65-2.91 (2H, m), 3.05 (1H, d, J=4.0 Hz), 3.97-4.17 (1H, m), 4.35(1H, br s), 4.92-5.04 (1H, m), 5.14 (1H, s), 6.21 (1H, d, J=8.6 Hz),6.70 (1H, br s), 7.03-7.55 (16H, m), 7.73 (2H, d, J=8.6 Hz); IR (KBr)3212, 3056, 1628, 1512, 1329, 1227, 1165, 1117, 1069, 762 cm⁻¹; Anal.Calcd for C₃₄H₂₇F₄NO₂S: C, 69.26; H, 4.62; N, 2.38. Found: C, 69.45; H,4.93; N, 2.22.

Example 98N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-1-methyl-1H-indole-3-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.172 g, 0.549 mmol), 1-methylindole-3-carboxylic acid (0.10 g, 0.55mmol) and 1-hydroxybenzotriazole hydrate (84 mg, 0.55 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.11 g, 0.55 mmol) was added and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solution,dried over anhydrous magnesium sulfate and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=2/1-1/1). Crystallizationfrom diethyl ether-hexane gave the objective substance.

white crystal yield 0.183 g, 71% mp 129-131° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.91 (1H, dd, J=9.5 Hz, 13.9 Hz), 3.01 (1H, dd, J=5.2 Hz, 14.8 Hz),3.76 (3H, s), 4.58-4.71 (1H, m), 4.73 (1H, br s), 5.10 (1H, br s), 5.89(1H, d, J=7.8 Hz), 7.05 (2H, t, J=8.8 Hz), 7.11-7.19 (1H, m), 7.23-7.30(4H, m), 7.36-7.51 (6H, m); IR (KBr) 3328, 1624, 1545, 1508, 1325, 1229,1163, 1128, 1067, 747 cm⁻¹; Anal. Calcd for C₂₆H₂₂F₄N₂O₂: C, 66.38; H,4.71; N, 5.95. Found: C, 66.27; H, 4.71; N, 5.82.

Example 99N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-5-phenylpentanamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 5-phenylpentanoicacid (257 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (413 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (220mg, 1.44 mmol) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (100 ml) andextracted with ethyl acetate (100 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:1). Recrystallization from ethylacetate-hexane gave the title compound (471 mg, 69%).

mp 152-153° C. IR ν max^(Kbr)cm⁻¹: 1647, 1549, 1512. Anal. Calcd forC₂₇H₂₇F₄NO₂: C, 68.49; H, 5.75; N, 2.96. Found: C, 68.39; H, 5.52; N,2.78. ¹H-NMR (CDCl₃)δ: 1.40-1.56 (4H, m), 2.00-2.16 (2H, m), 2.48-2.64(2H, m), 2.64-2.94 (2H, m), 3.52 (1H, d, J=3.8 Hz), 4.32-4.50 (1H, m),4.90-5.00 (1H, m), 5.36 (1H, d, J=8.4 Hz) 7.00-7.56 (13H, m).

Example 100 1,1-dimethylethyl(1S)-2-(((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)amino)-2-oxo-1-(phenylmethyl)ethylcarbamate

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in acetonitrile (30 ml) were addedN-t-butyloxycarbonyl-L-phenylalanine (382 mg, 1.44 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (413 mg,2.15 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate).Recrystallization from ethyl acetate-hexane gave the title compound (315mg, 39%).

mp 230-231° C. IR ν max^(KBr)cm⁻¹: 1678, 1659, 1524. ¹H-NMR (CDCl₃)δ:1.36 (9H, s), 2.60-2.90 (4H, m), 3.78-3.90 (4H, m), 4.10-4.40 (2H, m),4.60-4.68 (1H, m), 5.50 (1H, d, J=8.8 Hz), 6.96-7.50 (13H, m).

Example 101N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-4-methoxynaphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.174 g, 0.555 mmol), 4-methoxy-1-naphthoate (0.11 g, 0.56 mmol) and1-hydroxybenzotriazole hydrate (85 mg, 0.56 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11g, 0.56 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas, evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white crystal yield 0.209 g, 76% mp 227-228° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 88-3.20 (2H, m), 4.00 (3H, s), 4.60-4.75 (1H, m), 4.93 (1H,t, J=4.2 Hz), 5.49 (1H, d, J=3.6 Hz), 6.72 (1H, d, J=8.0 Hz), 7.03-7.19(3H, m), 7.29-7.71 (10H, m), 8.19 (1H, d, J=7.8 Hz); IR (KBr) 3281,1636, 1588, 1530, 1512, 1327, 1265, 1167, 1125, 1069, 839 cm⁻¹; Anal.Calcd for C₂₈H₂₃F₄NO₃: C, 67.60; H, 4.66; N, 2.82. Found: C, 67.58; H,4.83; N, 2.73.

Example 102N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-3-nitronaphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.174 g, 0.555 mmol) 3-nitro-1-naphthoate (0.12 g, 0.56 mmol) and1-hydroxybenzotriazole hydrate (85 mg, 0.56 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11g, 0.56 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under-reduced ressure and the obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

pale-yellow crystal yield 0.239 g, 84% mp 231-232° C.; ¹H-NMR(CDCl₃-DMSO-d₆, 200 MHz) δ 2.92 (1H, dd, J=11.4 Hz, 14.0 Hz), 3.20 (1H,dd, J=3.6 Hz, 13.0 Hz), 4.65-4.79 (1H, m), 4.94 (1H, t, J=4.5 Hz), 5.53(1H, d, J=4.4 Hz), 7.10 (2H, t, J=8.6 Hz), 7.36-7.66 (9H, m), 7.95 (1H,d, J=2.6 Hz), 8.03 (1H, d, J=8.0 Hz), 8.18 (1H, d, J=9.2 Hz), 8.78 (1H,d, J=2.2 Hz); IR (KBr) 3283, 1642, 1537, 1327, 1123, 1169, 835 cm⁻¹;Anal. Calcd for C₂₇H₂₀F₄N₂O₄: C, 63.28; H, 3.93; N, 5.47. Found: C,63.23; H, 3.65; N, 5.73.

Example 103 methyl4-[[[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]amino]carbonyl]-1-naphthoate

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.287 g, 0.916 mmol), 4-(methoxycarbonyl)-1-naphthoate (0.21 g, 0.92mmol) and 1-hydroxybenzotriazole hydrate (0.14 g, 0.92 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.18 g, 0.92 mmol) was added and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solution,dried over anhydrous magnesium sulfate and passed through silica gel.The solvent was evaporated under reduced pressure and the obtainedresidue was crystallized from ethyl acetate-hexane to give the objectivesubstance.

white amorphous powder yield 0.449 g, 93% ¹H-NMR (CDCl₃-DMSO-d₆, 200MHz) δ 2.92 (1H, dd, J=11.0 Hz, 14.0 Hz), 3.17 (1H, dd, J=3.2 Hz, 14.0Hz), 3.99 (3H, s), 4.72-4.85 (1H, m), 4.93 (1H, d, J=5.4 Hz), 5.35 (1H,br s), 7.09 (2H, t, J=8.6 Hz), 7.13 (1H, d, J=7.4 Hz), 7.26-7.42 (4H,m), 7.52-7.60 (5H, m), 7.86 (1H, d, J=9.2 Hz), 8.03 (1H, d, J=7.2 Hz),8.77 (1H, d, J=8.8 Hz); IR (KBr) 3283, 1721, 1640, 1512, 1327, 1254,1163, 1123, 1069, 839 cm¹; Anal. Calcd for C₂₉H₂₃F₄NO₄: C, 66.28; H,4.41; N, 2.67. Found: C, 66.06; H, 4.49; N, 2.58.

Example 104N1-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]naphthalene-1,4-dicarboxamide

1) 4-(aminocarbonyl)-1-naphthoate

To a solution of methyl 4-(aminocarbonyl)-1-naphthoate (0.499 g, 2.177mmol) in methanol (20 ml) and tetrahydrofuran (20 ml) was added 1Naqueous sodium hydroxide solution (6.53 ml, 6.53 mmol) and the mixturewas stirred overnight at room temperature. The reaction solution wasconcentrated, diluted with water and acidified with dilute hydrochloricacid. The resulting precipitate was collected by filtration and washedwith water and hexane to give the objective substance.

white powder yield 0.340 g, 73% mp 294-295° C.; ¹H-NMR (DMSO-d₆, 200MHz) δ 7.58-7.71 (3H, m), 7.76 (1H, br s), 8.10-8.13 (2H, m), 8.25-8.30(1H, m), 8.84-8.89 (1H, m); IR (KBr) 3191, 3300-2500, 1694, 1466, 1410,1368, 1325, 1294, 1264, 770 cm⁻¹; Anal. Calcd for C₁₂H₉NO₃: C, 66.97; H,4.22; N, 6.51. Found: C, 66.85; H, 4.11; N, 6.68.

2)N1-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]naphthalene-1,4-dicarboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.154 g, 0.492 mmol), 4-(aminocarbonyl)-1-naphthoate (0.11 g, 0.49mmol) and 1-hydroxybenzotriazole hydrate (75 mg, 0.49 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (94 mg, 0.49 mmol) was added and the mixture was stirredovernight at room temperature. The reaction solution was diluted withwater, the resulting precipitate was collected by filtration and washedwith water and diethyl ether to give the objective substance.

white powder yield 0.221 g, 88% mp 255-256° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.86-2.97 (1H, m), 3.15-3.24 (1H, m), 4.67-4.81 (1H, m), 4.89(1H, t, J=5.0 Hz), 5.46 (1H, d, J=4.0 Hz), 6.89 (1H, br s), 7.08 (2H, t,J=8.8 Hz), 7.11 (1H, d, J=7.0 Hz), 7.29-7.58. (11H, m), 7.94 (1H, d,J=9.2 Hz), 8.32 (1H, d, J=8.4 Hz); IR (KBr) 3283, 1638, 1510, 1329,1161, 1123, 1069, 837 cm⁻¹; Anal. Calcd for C₂₈H₂₂F₄N₂O₃.0.5H₂O: C,64.74; H, 4.46; N, 5.39. Found: C, 64.60; H, 4.72; N, 5.42.

Example 105N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-(hydroxymethyl)-1-naphthalenecarboxamide

1) To a solution of methyl 4-(hydroxymethyl)-1-naphthalenecarboxylate(700 mg, 3.24 mmol) in methanol (10 ml) was added 1N aqueous sodiumhydroxide solution (3.24 ml, 3.24 mmol) and the mixture was stirredovernight at room temperature. 1N Hydrochloric acid was added to thereaction solution (5 ml) and the mixture was extracted with ethylacetate (50 ml×2). The extract was washed with saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was recrystallized from ethyl acetate-hexane to give4-(hydroxymethyl)-1-naphthalenecarboxylic acid (570 mg, 87%).

mp 183-184° C. IR ν max^(KBr)cm⁻¹: 1694, 1593, 1518. ¹H-NMR (CDCl₃)δ:5.02 (2H, s), 7.54-7.70 (3H, m), 8.04-8.18 (2H, m), 8.86-8.98 (1H, m).

2) To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(300 mg, 0.96 mmol) in acetonitrile (30 ml) were added4-(hydroxymethyl)-1-naphthalenecarboxylic acid (194 mg, 0.96 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (275 mg,1.44 mmol) and 1-hydroxy-1H-benzotriazole (147 mg, 0.96 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml), and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane: ethylacetate=2:1). Recrystallization from ethyl acetate-hexane gave the titlecompound (365 mg, 77%).

mp 202-203° C. IR ν max^(KBr)cm⁻¹: 1638, 1618, 1605, 1537. Anal. Calcdfor C₂₈H₂₃F₄NO₃: C, 67.60; H, 4.66; N, 2.82. Found: C, 67.41; H, 4.64;N, 2.53. ¹H-NMR (CDCl₃)δ: 1.88 (1H, br s), 2.87 (1H, dd, J=14.4, 10.6Hz), 3.09 (1H, dd, J=14.4, 4.4 Hz), 4.72-4.90 (1H, m), 5.02-5.16 (3H,m), 5.94 (1H, d, J=8.0 Hz), 7.04-7.66 (13H, m), 8.02 (1H, d, J=8.4 Hz).

Example 1064-[[[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]amino]carbonyl]-1-naphthoate

To a solution of methyl4-[[[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]amino]carbonyl]-1-naphthoate(0.216 g, 0.411 mmol) in methanol (5 ml)—tetrahydrofuran (5 ml) wasadded 1N aqueous sodium hydroxide solution (1.64 ml, 1.64 mmol) and themixture was stirred at room temperature for 5 hrs. The reaction solutionwas concentrated, diluted with water and acidified with dilutehydrochloric acid. The resulting precipitate was collected by filtrationand washed with water and hexane to give the objective substance.

white powder yield 0.148 g, 70% mp 209-212° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.92 (1H, dd, J=11.2 Hz, 14.0 Hz), 3.14 (1H, dd, J=3.1 Hz,13.7 Hz), 4.71-4.86 (1H, m), 4.95 (1H, d, J=3.6 Hz), 5.31 (1H, br s),7.09 (2H, t, J=8.8 Hz), 7.16 (1H, d, J=7.4 Hz), 7.31-7.41 (4H, m),7.50-7.59 (5H, m), 7.79 (1H, d, J=9.8 Hz), 8.08 (1H, d, J=7.4 Hz), 8.91(1H, 6, J=8.8 Hz); IR (KBr) 3281, 1690, 1640, 1532, 1512, 1329, 1233,1165, 1125, 1069, 837 cm⁻¹; Anal. Calcd for C₂₈H₂₁F₄NO₄.1.0H₂O: C,63.52; H, 4.38; N, 2.65. Found: C, 63.45; H, 4.53; N, 2.49.

Example 107N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-3-phenoxybenzamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(400 mg, 1.28 mmol) in acetonitrile (20 ml) were added 3-phenoxybenzoicacid (274 mg, 1.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (368 mg, 1.92 mmol) and 1-hydroxy-1H-benzotriazole (196mg, 1.28 mmol) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (100 ml) andextracted with ethyl acetate (100 ml×2). The extract was washedsuccessively with 1N hydrochloric acid, 1N aqueous sodium hydroxidesolution and saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the title compound (400 mg, 61%).

mp 144-145° C. IR ν max^(KBr)cm⁻¹: 1644, 1580, 1510, 1491, 1481. Anal.Calcd for C₂₉H₂₃F₄NO₃.0.1H₂O: C, 68.13; H, 4.57; N, 2.74. Found: C,67.85; H, 4.51; N, 2.53. ¹H-NMR (CDCl₃)δ: 2.80-3.00 (2H, m), 3.30-3.70(1H, m), 4.50-4.64 (1H, m), 5.05 (1H, d, J=3.2 Hz), 6.11 (1H, d, J=8.6Hz), 6.96-7.52 (17H, m).

Example 108N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-phenoxybenzamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(400 mg, 1.28 mmol) in acetonitrile (20 ml) were added 4-phenoxybenzoicacid (274 mg, 1.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (368 mg, 1.92 mmol) and 1-hydroxy-1H-benzotriazole (196mg, 1.28 mmol) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (100 ml) andextracted with ethyl acetate (100 ml×2). The extract was washedsuccessively with 1N hydrochloric acid, 1N aqueous sodium hydroxidesolution and saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the title compound (451 mg, 69%).

mp 186-187° C. IR ν max^(KBr)cm⁻¹: 1622, 1609, 1590, 1532, 1510, 1501,1489. ¹H-NMR (CDCl₃)δ: 2.80-3.02 (2H, m), 3.80-4.00 (1H, m), 4.50-4.70(1H, m), 5.06 (1H, d, J=3.2 Hz), 6.17 (1H, d, J=8.4 Hz), 6.90-7.60 (17H,m).

Example 109N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-3,3,3-trifluoropropionamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.166 g, 0.530 mmol), 3,3,3-trifluoropropionic acid (68 mg, 0.53 mmol)and 1-hydroxybenzotriazole hydrate (81 mg, 0.53 mmol) in acetonitrile(10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(0.10 g, 0.53 mmol) was added and the mixture was stirred overnight atroom temperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from hexane to give the objective substance.

white crystal yield 0.185 g, 83% mp 179-180° C; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.79-2.83 (2H, m), 2.90 (1H, d, J=10.6 Hz), 3.01 (1H, d,J=10.6 Hz), 4.35-4.49 (1H, m), 4.64 (1H, d, J=3.2 Hz), 4.93 (1H, t,J=3.4 Hz), 7.06 (2H, t, J=8.6 Hz), 7.17-7.21 (3H, m), 7.40-7.47 (4H, m);IR (KBr) 3308, 1663, 1514, 1327, 1238, 1175, 1113, 1069, 831 cm⁻¹; Anal.Calcd for C₁₉H₁₆F₇NO₂: C, 53.91; H, 3.81; N, 3.31. Found: C, 53;84; H,3.61; N, 3.13.

Example 1102-cyclopentyl-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-2-phenylacetamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.156 g, 0.498 mmol), 2-cyclopentyl-2-phenylacetic acid (0.10 g, 0.50mmol) and 1-hydroxybenzotriazole hydrate (76 mg, 0.50 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (95 mg, 0.50 mmol) was added and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solution,dried over anhydrous magnesium sulfate and passed through silica gel.The solvent was evaporated under reduced pressure and the obtainedresidue was crystallized from diisopropyl ether-hexane to give theobjective substance.

white crystal yield 0.208 g, 84% mp 201-202° C; ¹H-NMR (CDCl₃, 200 MHz)δ 0.73-1.08 (2H, m), 1.30-1.70 (6H, m), 2.38-2.93 (4H, m), 3.43 (0.5H,d, J=3.6 Hz), 3.53 (0.5H, d, J=3.6 Hz), 4.34-4.48 (1H, m), 4.80-4.85(1H, m), 5.23 (0.5H, br d, J=8.4 Hz), 5.34 (0.5H, br d, J=6.6 Hz),6.88-7.31 (12H, m), 7.43 (1H, d, J=8.0 Hz); IR (KBr) 3316, 2957, 1645,1530, 1514, 1327, 1233, 1167, 1123, 1069, 831 cm⁻¹; Anal. Calcd forC₂₉H₂₉F₄NO₂: C, 69.73; H, 5.8.5; N, 2.80. Found: C, 69.71; H, 5.95; N,2.63.

Example 111N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-3-nitro-5,6,7,8-tetrahydronaphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.150 g, 0.479 mmol),3-nitro-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid (see Chem.Pharm. Bull., 32, 3968-80 (1984)) (0.11 g, 0.48 mmol) and1-hydroxybenzotriazole hydrate (73 mg, 0.48 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (92 mg,0.48 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from ethyl acetate-diisopropyl ether-hexane to give theobjective substance.

white crystal yield 0.180 g, 73% mp 216-217° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 1.49-1.78 (4H, m), 1.97-2.13 (1H, m), 2.36-2.52 (1H, m),2.77-2.93 (3H, m), 3.02 (1H, dd, J=4.3 Hz, 14.5 Hz), 4.58-4.73 (1H, m),4.96 (1H, t, J=4.2 Hz), 5.28 (1H, d, J=3.6 Hz), 7.08 (2H, t, J=8.8 Hz),7.30-7.56 (6H, m), 7.72 (1H, d, J=2.2 Hz), 7.89 (1H, d, J=2.2 Hz); IR(KBr) 3260, 1642, 1534, 1514, 1346, 1327, 1231, 1165, 1123, 1067, 837cm⁻¹; Anal. Calcd for C₂₇H₂₄F₄N₂O₄: C, 62.79; H, 4.68; N, 5.42. Found:C, 62.68; H, 4.45; N, 5.33.

Example 1122-benzyl-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-3,3-dimethylbutyramide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.264 g, 0.843 mmol), 2-benzyl-3,3-dimethylbutanoic acid (0.17 g, 0.84mmol), 4-N,N-dimethylaminopyridine (0.10 g, 0.84 mmol) and1-hydroxybenzotriazole hydrate (0.13 g, 0.84 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.16g, 0.84 mmol) was added and the mixture was stirred at 60° C. for 3days. The reaction solution was diluted with ethyl acetate, washed withaqueous sodium hydrogen carbonate solution, dried over anhydrousmagnesium sulfate and passed through silica gel. The solvent wasevaporated under reduced pressure. The obtained residue was crystallizedfrom diisopropyl ether-hexane to give the objective substance.

white crystal yield 0.206 g, 49% mp 175-176° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 0.76 (3.5H, s), 0.90 (5.5 H, s), 1.80-1.93 (1H, m), 2.15-3.02 (5H, m),4.25-4.40 (1H, m), 4.48-4.53 (1H, m), 4.92-5.04 (1H, m), 6.76-7.45 (13H,m); IR (KBr) 3551, 2967, 1651, 1507, 1333, 1154, 1127, 1123, 1069, 835cm⁻¹; Anal. Calcd for C₂₉H₃₁F₄NO₂: C, 69.45; H, 6.23; N, 2.79. Found: C,69.09; H, 6.28; N, 2.80.

Example 113N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-3,4-dihydro-2H-1,5-benzodioxepine-6-carboxamide

1) methyl 2,3-dihydroxybenzoate

2,3-Dihydroxybenzoic acid (5.029 g, 32.63 mmol) was heated under refluxin a solution (80 ml) of 10% hydrogen chloride in methanol for 3 days.The solvent of the reaction solution was evaporated under reducedpressure, diluted with water and extracted with ethyl acetate. Theobtained ethyl acetate solution was dried over anhydrous magnesiumsulfate and passed through silica gel. The solvent was evaporated underreduced pressure. The obtained residue was crystallized from colddiisopropyl ether-hexane to give the objective substance.

brown crystal yield 4.439 g, 81% mp 77-78° C.; ¹H-NMR (CDCl₃, 200 MHz) δ3.96 (3H, s), 5.65 (1H, s), 6.80 (1H, t, J=8.1 Hz), 7.11 (1H, dd, J=1.5Hz, 7.7 Hz), 7.37 (1H, dd, J=1.1 Hz, 8.1 Hz), 10.89 (1H, s); IR (KBr)3465, 3100 2850, 1674, 1468, 1437, 1321, 1269, 1194, 1152, 1076, 1009,837, 758 cm⁻¹; Anal. Calcd for C₈H₈O₄: C, 57.14; H, 4.80. Found: C,56.93; H, 4.94.

2) methyl 3,4-dihydro-2H-1,5-benzodioxepine-6-carboxylate

Methyl 2,3-dihydroxybenzoate (1.870 g, 11.12 mmol), 1,3-dibromopropane(2.25 g, 11.1 mmol) and potassium carbonate (6.15 g, 44.5 mmol) werestirred in N,N-dimethylformamide (20 ml) overnight at 60° C. Thereaction solution was poured into water and extracted twice with ethylacetate. The collected organic layer was dried over anhydrous sodiumsulfate and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=6/1−3/1) to give the objective substance.

colorless liquid yield 1.711 g, 74% ¹H-NMR (CDCl₃, 200 MHz) δ 2.18-2.29(2H, m), 3.89 (3H, s), 4.25 (2H, t, J=5.7 Hz), 4.30 (2H, t, J=5.7 Hz),6.95 (1H, t, J=7.9 Hz), 7.12 (1H, dd, J=1.8 Hz, 8.0 Hz), 7.36 (1H, dd,J=1.8 Hz, 7.8 Hz); IR (neat) 2953, 1732, 1478, 1454, 1296, 1262, 1225,1138, 1080, 1044 cm⁻¹

3) 3,4-dihydro-2H-1,5-benzodioxepine-6-carboxylic acid

To a solution of methyl 3,4-dihydro-2H-1,5-benzodioxepine-6-carboxylate(1.615 g, 7.757 mmol) in methanol (20 ml)—tetrahydrofuran (10 ml) wasadded 1N aqueous sodium hydroxide solution (15.5 ml, 15.5 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas concentrated, diluted with water, acidified with dilute hydrochloricacid and extracted twice with ethyl acetate. The collected organic layerwas dried over anhydrous sodium sulfate and the solvent was evaporatedunder reduced pressure. The residue was crystallized from hexane to givethe objective substance.

white crystal yield 1.376 g, 91% mp 68-70° C.; ¹H-NMR (CDCl₃, 200 MHz) δ2.29-2.40 (2H, m), 4.30 (2H, t, J=5.8 Hz), 4.52 (2H, t, J=5.6 Hz), 7.09(1H, t, J=7.9 Hz), 7.24 (1H, dd, J=2.0 Hz, 8.2 Hz), 7.85 (1H, dd, J=1.8Hz, 7.6 Hz); IR (KBr) 3171, 1725, 1478, 1348, 1264, 1022, 752 cm⁻¹;Anal. Calcd for C₁₀H₁₀O₄: C, 61.85; H, 5.19. Found: C, 61.77; H, 5.49.

4)N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-3,4-dihydro-2H-1,5-benzodioxepine-6-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.262 g, 0.836 mmol), 3,4-dihydro-2H-1,5-benzodioxepine-6-carboxylicacid (0.16 g, 0.84 mmol) and 1-hydroxybenzotriazole hydrate (0.13 g,0.84 mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.16 g,0.84 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white crystal yield 0.361 g, 88% mp 155-156° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.05-2.16 (2H, m), 2.93-2.97 (2H, m), 3.69-3.86 (2H, m), 4.09-4.20(3H, m), 4.55-4.67 (1H, m), 5.10 (1H, t, J=3.3 Hz), 6.98-7.15 (4H, m),7.26 (2H, d, J=7.8 Hz), 7.38-7.52 (4H, m), 7.76 (1H, dd, J=1.8 Hz, 7.8Hz), 7.92 (1H, br d, J=7.8 Hz); IR (KBr) 3279, 1636, 1541, 1512, 1325,1264, 1231, 1169, 1121, 1069, 1044, 837 cm⁻¹; Anal. Calcd forC₂₆H₂₃F₄NO₄: C, 63.80; H, 4.74; N, 2.86. Found: C, 63.63; H, 4.72; N,2.80.

Example 114 benzylN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]carbamate

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.159 g, 0.508 mmol) and sodium hydrogen carbonate (85 mg, 1.02 mmol)in tetrahydrofuran (10 ml), benzyl chlorocarbonate (0.09 ml, 0.61 mmol)was added and the mixture was stirred overnight at room temperature. Thereaction solution was diluted with ethyl acetate, washed with aqueoussodium hydrogen carbonate solution, dried over anhydrous magnesiumsulfate and passed through silica gel. The solvent was evaporated underreduced pressure. The obtained residue was crystallized from diisopropylether-hexane to give the objective substance.

white crystal yield 0.190 g, 84% mp 151-152° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.68-2.91 (3H, m), 4.08-4.22 (1H, m), 4.81 (1H, br d, J=8.8 Hz), 4.94(1H, br s), 5.00 (2H, s), 7.06 (2H, t, J=8.6 Hz), 7.17-7.40 (9H, m),7.48 (2H, d, J=7.8 Hz); IR (KBr) 3337, 1694, 1539, 1327, 1163, 1121,1069, 829 cm⁻¹; Anal. Calcd for C₂₄H₂₁F₄NO₃: C, 64.43; H, 4.73; N, 3.13.Found: C, 64.46; H, 4.77; N, 2.94.

Example 115 ethylN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]carbamate

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.401 g, 1.280 mmol) and sodium hydrogen carbonate (0.22 g, 2.56 mmol)in tetrahydrofuran (10 ml)—water (2 ml), ethyl chlorocarbonate (0.15 ml,1.54 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white crystal yield 0.413 g, 84% mp 143-144° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.15 (3H, t, J=7.0 Hz), 2.67-2.95 (3H, m), 3.93-4.20 (3H, m), 4.71(1H, d, J=8.6 Hz), 4.95 (1H, s), 7.08 (2H, t, J=8.6 Hz), 7.21 (2H, d,J=8.0 Hz), 7.39 (2H, dd, J=5.5 Hz, 8.5 Hz), 7.51 (2H, d, J=8.0 Hz); IR(KBr) 3318, 1690, 1547, 1329, 1163, 1117, 1069, 829 cm⁻¹; Anal. Calcdfor C₁₉H₁₉F₄NO₃: C, 59.22; H, 4.97;, N, 3.63. Found: C, 59.28; H, 5.10;N, 3.63.

Example 116 neopentylN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]carbamate

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.171 g, 0.546 mmol) and sodium hydrogen carbonate (92 mg, 1.09 mmol)in tetrahydrofuran (10 ml), neopentyl chlorocarbonate (0.10 ml, 0.65mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from hexane to give the objective substance.

white crystal yield 0.168 g, 72% mp 112-113° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 0.82 (9H, s), 2.66-2.92 (3H, m), 3.67 (2H, br s), 4.14 (1H, br s),4.72 (1H, br d, J=8.2 Hz), 4.95 (1H, br s), 7.08 (2H, t, J=8.6 Hz), 7.22(2H, d, J=8.0 Hz), 7.39 (2H, dd, J=5.2 Hz, 8.4 Hz), 7.50 (2H, d, J=8.0Hz); IR (KBr) 3326, 2967, 1690, 1545, 1327, 1127, 1069, 833 cm⁻¹; Anal.Calcd for C₂₂H₂₅F₄NO₃: C, 61.82; H, 5.90; N, 3.28. Found: C, 61.47; H,5.85; N, 3.04.

Example 117N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenesulfonamide

To a solution of(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.43 mmol) in ethyl acetate (5 ml) were added1-naphthalenesulfonyl chloride (107 mg, 0.47 mmol) and saturated aqueoussodium hydrogen carbonate (5 ml) and the mixture was stirred overnightat room temperature. The reaction solution was diluted with water (50ml) and extracted with ethyl acetate (50 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1). Recrystallizationfrom ethyl acetate-hexane gave the title compound (109 mg, 50%).

mp 176-177° C. IR ν max^(KBr)cm⁻¹: 1508, 1325, 1223, 1161, 1129. Anal.Calcd for C₂₆H₂₁F₄NO₃S: C, 62.02; H, 4.20; N, 2.78. Found: C, 61.73; H,4.20; N, 2.74. ¹H-NMR (CDCl₃)δ: 2.40-2.62 (2H, m), 2.95 (1H, br s),3.56-3.70 (1H, m), 5.15 (2H, s), 6.60 (2H, d, J=8.0 Hz), 6.79 (2H, d,J=8.0 Hz), 6.90-7.04 (2H, m), 7.20-7.40 (3H, m), 7.40-7.56 (2H, m),7.70-7.84 (1H, m), 7.91 (1H, d, J=8.0 Hz), 8.05 (1H, d, J=8.0 Hz),8.20-8.30 (1H, m).

Example 118N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-N′-(1-naphthalenyl)urea

To a solution of(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.43 mmol) in acetonitrile (10 ml) were addedtriethylamine (0.089 ml, 0.64 mmol) and 1-naphthyl isocyanate (0.062 ml,0.43 mmol) and the mixture was stirred overnight at room temperature.The reaction solution was diluted with water (50 ml) and extracted withethyl acetate (50 ml×2). The extract was washed successively with 1Nhydrochloric acid, 1N aqueous sodium hydroxide solution and saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was recrystallized from ethylacetate-hexane to give the title compound (135 mg, 65%).

mp 222-223° C. IR ν max^(KBr)cm⁻¹: 1661, 1638, 1557, 1510. Anal. Calcdfor C₂₇H₂₂F₄N₂O₂: C, 67.21; H, 4.60; N, 5.81. Found: C, 67.02; H, 4.47;N, 5.78. ¹H-NMR (CDCl₃)δ: 2.47 (1H, dd, J=14.4, 10.0 Hz), 2.78 (1H, dd,J=14.4, 3.6 Hz), 4.20-4.40 (3H, m), 4.91 (1H, br s), 6.36 (1H, s),6.92-7.10 (5H, m), 7.22-7.40 (5H, m), 7.40-7.58 (2H, m), 7.74-7.94 (3H,m).

Example 119N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-N′-(4-(trifluoromethyl)phenyl)urea

To a solution of(1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.43 mmol) in acetonitrile (10 ml) were addedtriethylamine (0.089 ml, 0.64 mmol) and 4-trifluoromethylphenylisocyanate (0.061 ml, 0.43 mmol) and the mixture was stirred overnightat room temperature. The reaction solution was diluted with water (50ml) and extracted with ethyl acetate (50 ml×2). The extract was washedsuccessively with 1N hydrochloric acid, 1N aqueous sodium hydroxidesolution and saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the title compound (139 mg, 65%).

mp 160-161° C. IR ν max^(KBr)cm⁻¹: 1659, 1605, 1557, 1508. Anal. Calcdfor C₂₄H₁₉F₇N₂O₂: C, 57.60; H, 3.83; N, 5.60. Found: C, 57.61; H, 3.59;N, 5.65. ¹H-NMR (CDCl₃)δ: 2.60-2.92 (2H, m), 3.50 (1H, br s), 4.22-4.50(1H, m), 4.80 (1H, d, J=8.0 Hz), 5.01 (1H, s), 6.75 (1H, s), 7.00-7.18(2H, m), 7.18-7.60 (10H, m).

Example 120N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-N-(1-naphthalenylmethyl)acetamide

1) To a solution of(4RS,5SR)-5-(4-fluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(1 g, 2.95 mmol) in N,N-dimethylformamide (10 ml) was added 60% sodiumhydride (142 mg, 3.54 mmol) and the mixture was stirred at roomtemperature for 15 min. To the reaction solution was added1-naphthylmethyl chloride (480 ml, 3.25 mmol) and the mixture wasstirred for 1 hr. The reaction solution was diluted with water (100 ml)and extracted with ethyl acetate (100 ml×2). The extract was washed withwater and saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1). Recrystallizationfrom diisopropyl ether-hexane gave(4RS,5SR)-5-(4-fluorophenyl)-3-(1-naphthalenylmethyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(1.23 g, 87%).

mp 136-137° C. IR ν max^(KBr)cm⁻¹: 1748, 1609. Anal. Calcd forC₂₈H₂₁F₄NO₂: C, 70.14; H, 4.41; N, 2.92. Found: C, 70.15; H, 4.23; N,2.78. ¹H-NMR (CDCl₃)δ: 2.34 (1H, dd, J=14.4, 8.0 Hz), 2.81 (1H, dd,J=14.4, 5.2 Hz), 3.70-3.84 (1H, m), 4.24 (1H, d, J=15.2 Hz), 5.28 (1H,d, J=7.6 Hz), 5.40 (1H, d, J=15.2 Hz), 6.48 (2H, d, J=8.2 Hz), 6.76-7.10(5H, m), 7.14-7.56 (5H, m), 7.70-8.00 (3H, m).

2) To a solution of(4RS,5SR)-5-(4-fluorophenyl)-3-(1-naphthalenylmethyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(100 mg, 0.21 mmol) in ethanol (2 ml) was added 8N aqueous sodiumhydroxide solution (130 ml) and the mixture was heated under reflux for4 hrs. The reaction solution was diluted with water (50 ml) andextracted with ethyl acetate (50 ml×2). The extract was washed withwater and saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=2:1). Recrystallizationfrom diisopropyl ether-hexane gave(1RS,2SR)-1-(4-fluorophenyl)-2-((1-naphthalenylmethyl)amino)-3-(4-(trifluoromethyl)phenyl)-1-propanol(29.6 mg, 31%).

mp 94-95° C. IR ν max^(KBr)cm⁻¹: 1605, 1510, 1325. Anal. Calcd forC₂₇H₂₃F₄NO: C, 71.51; H, 5.11; N, 3.09. Found: C, 71.40; H, 5.07; N,2.98. ¹H-NMR (CDCl₃)δ: 2.45 (2H, d, J=7.4 Hz), 3.02-3.14 (1H, m), 3.71(1H, br s), 4.03 (1H, d, J=13.2 Hz), 4.33 (1H, d, J=13.2 Hz), 5.06 (1H,d, J=3.6 Hz), 6.92 (2H, d, J=7.6 Hz), 7.00-7.16 (2H, m), 7.20-7.58 (9H,m), 7.70-7.88 (2H, m).

3) To a solution of(1RS,2SR)-1-(4-fluorophenyl)-2-((1-naphthalenylmethyl)amino)-3-(4-(trifluoromethyl)phenyl)-1-propanol(100 mg, 0.22 mmol) in ethyl acetate (5 ml) were added acetyl chloride(225 ml, 3.3 mmol) and saturated aqueous sodium hydrogen carbonate (5ml) and the mixture was stirred overnight at room temperature. Thereaction solution was diluted with water (50 ml) and extracted withethyl acetate (50 ml×2). The extract was washed with saturated brine,dried over anhydrous magnesium sulfate and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=1:1) to give the title compound (45 mg, 41%).

IR ν max^(KBr)cm⁻¹: 1622, 1508, 1456. ¹H-NMR (CDCl₃)δ: 2.32 (3H, s),2.73 (1H, d, J=11.0 Hz), 3.32-3.76 (3H, m), 4.76 (1H, s), 4.82 (1H, d,J=15.6 Hz), 6.50-6.64 (2H, m), 6.70-6.84 (2H, m), 7.00-7.18 (3H, m),7.40-7.60 (6H, m), 7.82-8.00 (2H, m).

Example 121N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-N-methyl-1-naphthalenecarboxamide

1) To a solution of(4RS,5SR)-5-(4-fluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(5 g, 14.7 mmol) in N,N-dimethylformamide (30 ml) was added 60% sodiumhydride (710 mg, 17.7 mmol) and the mixture was stirred at roomtemperature for 15 min. To the reaction solution was added methyl iodide(5 ml, 80 mmol) and the mixture was stirred for 1 hr. The reactionsolution was diluted with water (300 ml) and extracted with ethylacetate (200 ml×2). The extract was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was recrystallized from diisopropylether-hexane to give(4RS,5SR)-5-(4-fluorophenyl)-3-methyl-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(4.76 g, 91%).

mp 77-78° C. IR ν max^(KBr)cm⁻¹: 1759, 1609, 1514. Anal. Calcd forC₁₈H₁₅F₄NO₂: C, 61.19; H, 4.28; N, 3.96. Found: C, 61.25; H, 4.21; N,3.96. ¹H-NMR (CDCl₃)δ: 2.45 (1H, dd, J=14.2, 7.2 Hz), 2.77 (1H, dd,14.2, 7.2 Hz), 4.30 (1H, q, J=6.6 Hz), 5.59 (1H, d, J=8.0 Hz), 6.92 (2H,d, J=8.0 Hz), 6.94-7.08 (2H, m), 7.10-7.20 (2H, m), 7.44 (2H, d, J=8.0Hz).

2) To a solution of(4RS,5SR)-5-(4-fluorophenyl)-3-methyl-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(4.56 g, 12.9 mmol) in ethanol (20 ml) was added 8N aqueous sodiumhydroxide solution (8.07 ml) and the mixture was heated under reflux for3 hrs. The reaction solution was diluted with water (200 ml) andextracted with ethyl acetate (200 ml×2). The extract was washed withwater and saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromdiisopropyl ether-hexane to give(1RS,2SR)-1-(4-fluorophenyl)-2-(methylamino)-3-(4-(trifluoromethyl)phenyl)-1-propanol(3.34 mg, 79%).

mp 79-80° C. IR ν max^(KBr)cm⁻¹: 1618, 1605, 1510. Anal. Calcd forC₁₇H₁₇F₄NO: C, 62.38; H, 5.23; N, 4.28. Found: C, 62.38; H, 5.11; N,4.27. ¹H-NMR (CDCl₃)δ: 2.41 (3H, s), 2.44-2.60 (2H, m), 2.84-2.96 (1H,m), 4.94 (1H, d, J=3.2 Hz), 7.00-7.12 (2H, m), 7.18 (2H, d, J=8.0 Hz),7.32-7.50 (2H, m), 7.52 (2H, d, J=8.0 Hz).

3) To a solution of(1RS,2SR)-1-(4-fluorophenyl)-2-(methylamino)-3-(4-(trifluoromethyl)phenyl)-1-propanol(150 mg, 0.46 mmol) in ethyl acetate (5 ml) were added 1-naphthoylchloride (76 ml, 0.50 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml) and the mixture was stirred at room temperature for 6hrs. The reaction solution was diluted with water (50 ml) and extractedwith ethyl acetate (50 ml×2). The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1-1:1) and recrystallized fromethyl acetate-hexane to give the title compound (166 mg, 75%).

mp 196-197° C. IR ν max^(KBr)cm⁻¹: 1605, 1510, 1325. Anal. Calcd forC₂₈H₂₃F₄NO₂: C, 69.85; H, 4.81; N, 2.91. Found: C, 69.76; H, 4.89; N,2.80. ¹H-NMR (CDCl₃)δ: 2.48 (3H, d, J=4.4 Hz), 3.02-3.30 (1H, m),3.60-3.78 (1H, m), 6.08 (1H, d, J=8.6 Hz), 6.24-6.36 (1H, m), 7.00-7.50(6H, m), 7.58-7.80 (9H, m).

Example 122N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1) ethyl3-(4-fluorophenyl)-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate

A solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (6.70 g, 32.2 mmol),N-bromosuccinimide (5.73 g, 32.2 mmol) and 2,2′-azobis(isobutyronitrile)(10 mg) in carbon tetrachloride (30 ml) was heated under reflux for 0.5hr. After cooling the reaction solution to room-temperature, the whiteprecipitate was removed by filtration and the precipitate was washedwith diethyl ether. The solvent of the collected filtrate was evaporatedunder reduced pressure to give a crude product of3-(1,1,2,2-tetrafluoroethoxy)benzyl bromide as a pale-yellow liquid.

To a solution of ethyl (4-fluorobenzoyl)acetate (6.153 g, 29.27 mmol) in1,2-dimethoxyethane (50 ml) was added a suspension (1.17 g, 29.3 mmol)of 60% sodium hydride in liquid paraffin under ice-cooling and themixture was stirred as it as under ice-cooling for 0.5 hr. A solution of3-(1,1,2,2-tetrafluoroethoxy)benzyl bromide obtained above in1,2-dimethoxyethane (10 ml) was added thereto at room temperature, andthe mixture was stirred at room temperature for 8 hrs. The reactionsolution was poured into water and extracted twice with ethyl acetate.The collected organic layer was dried over anhydrous magnesium sulfateand the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane/ethylacetate=15/1-9/1). Crystallization from hexane gave the objectivesubstance.

white crystal yield 7.539 g, 62% mp 53-54° C.; ¹H-NMR (CDCl₃, 200 MHz) δ1.12 (3H, t, J=7.1 Hz), 3.34 (2H, d, J=7.6 Hz), 4.10 (2H, q, J=7.1 Hz),4.56 (1H, t, J=7.3 Hz), 5.89 (1H, tt, J=2.8 Hz, 53.1 Hz), 7.04-7.16 (5H,m), 7.27 (1H, t, J=7.7 Hz), 7.99 (2H, dd, J=5.5 Hz, 8.7 Hz); IR (KBr)1728, 1682, 1597, 1325, 1275, 1236, 1205, 1157, 1134, 1100, 847 cm⁻¹;Anal. Calcd for C₂₀H₁₇F₅O₄: C, 57.70; H, 4.12. Found: C, 57.71; H, 4.15.

2) ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate

While stirring zinc chloride (4.70 g, 34.5 mmol) in diethyl ether (80ml), sodium borohydride (2.61 g, 68.9 mmol) was added as it was at roomtemperature and the mixture was stirred as it was for 2 hrs. Theinsoluble material of the mixture was removed by filtration and washedwith diethyl ether to give a solution of zinc borohydride in diethylether. To the obtained solution was added a solution of ethyl3-(4-fluorophenyl)-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate(7.176 g, 17.24 mmol) in diethyl ether (30 ml) at room temperature andthe mixture was stirred as it was at room temperature for 2 hrs. Dilutehydrochloric acid was added to the solution by small portions todecompose excess zinc borohydride and the mixture was extracted twicewith ethyl acetate. The collected organic layer was dried over anhydrousmagnesium sulfate and the solvent was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=6/1−3/1) to give the objectivesubstance.

colorless liquid yield 7.295 g, 100% ¹H-NMR (CDCl₃, 200 MHz) δ 0.93 (3H,t, J=7.1 Hz), 2.90-3.04 (4H, m), 3.89 (2H, q, J=7.1 Hz), 5.02 (1H, t,J=3.6 Hz), 5.88 (1H, tt, J=2.9 Hz, 53.2 Hz), 6.95-7.10 (5H, m), 7.24(1H, t, J=7.8 Hz), 7.37 (2H, dd, J=5.5 Hz, 8.7 Hz); IR (neat) 3463,1725, 1510, 1302, 1279, 1227, 1198, 1159, 1123, 839 cm⁻¹

3)(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionicacid

To a solution of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate(7.252 g, 17.33 mmol) in methanol (30 ml)—tetrahydrofuran (30 ml) wasadded 1N aqueous sodium hydroxide solution (34.7 ml, 34.7 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas concentrated, diluted with water, acidified with 1N hydrochloricacid and extracted twice with ethyl acetate. The collected organic layerwas dried over anhydrous sodium sulfate and the solvent was evaporatedunder reduced pressure. The residue was crystallized from hexane to givethe objective substance.

white crystal yield 5.795 g, 86% mp 116-117° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.92-3.08 (3H, m), 5.06 (1H, s), 5.88 (1H, tt, J=2.9 Hz, 53.2 Hz),6.94-7.09 (5H, m), 7.23 (1H, t, J=7.9 Hz), 7.36 (2H, dd, J=5.4 Hz, 8.6Hz); IR (KBr) 3370-2850, 1713, 1229, 1206, 1186, 1115, 841 cm⁻¹; Anal.Calcd for C₁₈H₁₅F₅O₄: C, 55.39; H, 3.87. Found: C, 55.51; H, 3.68.

4)(4RS,5SR)-5-(4-fluorophenyl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionicacid (4.544 g, 11.64 mmol) in tetrahydrofuran (40 ml) were addedtriethylamine (2.43 ml, 17.5 mmol) and diphenylphosphoryl azide (3.52 g,12.8 mmol) and the mixture was heated under reflux overnight. Thesolvent of the reaction solution was evaporated under reduced pressureand the obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1). Crystallization fromdiethyl ether-hexane gave the objective substance.

white crystal yield 4.241 g, 94% mp 135-136° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.20-2.36 (2H, m), 4.26 (1H, dt, J=5.5 Hz, 8.6 Hz), 4.97 (1H, br s),5.80 (1H, d, J=8.2 Hz), 5.90 (1H, tt, J=2.8 Hz, 53.0 Hz), 6.88 (1H, s),6.95 (1H, d, J=7.6 Hz), 7.07-7.17 (3H, m), 7.31-7.39 (3H, m); IR (KBr)3241, 1740, 1514, 1236, 1223, 1196, 1144, 1127, 851 cm⁻¹; Anal. Calcdfor C₁₈H₁₄F₅NO₃: C, 55.82; H, 3.64; N, 3.62. Found: C, 55.96; H, 3.77;N, 3.38.

5)(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol

(4RS,5SR)-5-(4-Fluorophenyl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one(4.069 g, 10.51 mmol) and sodium hydroxide (1.68 g, 42.0 mmol) washeated under reflux in ethanol (30 ml)—water (2 ml) for 6 hrs. Thereaction solution was diluted with water and extracted twice with ethylacetate. The collected organic layer was dried over anhydrous sodiumsulfate and the solvent was evaporated under reduced pressure. Theresidue was crystallized from diisopropyl ether-hexane to give theobjective substance.

white crystal yield 2.961 g, 7.8% mp 87-88° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.38 (1H, dd, J=10.4 Hz, 13.8 Hz), 2.81 (1H, dd, J=3.0 Hz, 14.0 Hz),3.27 (1H, ddd, J=3.4 Hz, 4.9 Hz, 10.4 Hz), 4.65 (1H, d, J=5.2 Hz), 5.89(1H, tt, J=2.8 Hz, 53.1 Hz), 7.00-7.13 (5H, m), 7.30-7.40 (3H, m); IR(KBr) 3368, 3250-2720, 1508, 1211, 1199, 1127, 1101, 1044 cm⁻¹; Anal.Calcd for C₁₇H₁₆F₅NO₂: C, 56.51; H, 4.46; N, 3.88. Found: C, 56.43; H,4.50; N, 3.58.

6)N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(0.173 g, 0.479 mmol), 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylicacid (90 mg, 0.48 mmol) and 1-hydroxybenzotriazole hydrate (73 mg, 0.48mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (92 mg, 0.48mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white crystal yield 0.216 g, 85% mp 176-177° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.93-2.05 (2H, m), 2.15-2.24 (2H, m), 2.67 (2H, t, J=5.8 Hz), 2.78(1H, dd, J=10.8 Hz, 14.4 Hz), 3.00 (1H, dd, J=4.2 Hz, 14.4 Hz), 3.61(1H, d, J=3.6 Hz), 4.60-4.73 (1H, m), 5.03 (1H, t, J=3.8 Hz), 5.73 (1H,d, J=8.2 Hz), 5.88 (1H, tt, J=2.5 Hz, 53.1 Hz), 5.92 (1H, td, J=5.4 Hz,12.2 Hz), 6.20 (1H, d, J=11.8 Hz), 6.94-7.17 (8H, m), 7.30 (1H, t, J=7.8Hz), 7.43 (2H, dd, J=5.6 Hz, 8.4 Hz); IR (KBr) 3270, 1640, 1510, 1227,1198, 1127 cm⁻¹; Anal. Calcd for C₂₉H₂₆F₅NO₃: C, 65.53; H, 4.93; N,2.64. Found: C, 65.39; H, 4.84; N, 2.63.

Example 123N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-5,6-dihydronaphthalene-1-carboxamide

1) methyl 5,6-dihydronaphthalene-1-carboxylate

Methyl 8-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carboxylate (seeTetrahedron, 53, 15969-15982; (1990)) (5.029 g, 32.63 mmol) was heatedunder reflux in a solution (80 ml) of 10% hydrogen chloride in methanolovernight. The solvent of the reaction solution was evaporated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate=6/1) to give the objectivesubstance.

colorless liquid yield 0.239 g, 17% ¹H-NMR (CDCl₃, 200 MHz) δ 2.23-2.34(2H, m), 2.81 (2H, t, J=8.2 Hz), 3.89 (3H, s), 6.22 (1H, td, J=4.8 Hz,9.7 Hz), 7.14 (1H, t, J=7.5 Hz), 7.25 (1H, d, J=7.4 Hz), 7.33 (1H, td,J=1.6 Hz, 10.2 Hz), 7.69 (1H, dd, J=1.5 Hz, 7.7 Hz); IR (neat) 1721,1264, 1142, 781 cm⁻¹

2) 5,6-dihydronaphthalene-1-carboxylic acid

To a solution of methyl 5,6-dihydronaphthalene-1-carboxylate (0.276 g,1.466 mmol) in methanol (30 ml) was added 1N aqueous sodium hydroxidesolution (8.80 ml, 8.80 mmol) and the mixture was stirred at 70° C. for8 hrs. The reaction solution was diluted with water, acidified withdilute hydrochloric acid and extracted twice with ethyl acetate. Thecollected organic layer was dried over anhydrous sodium sulfate and thesolvent was evaporated under reduced pressure. The residue wascrystallized from hexane to give the objective substance.

white crystal yield 0.158 g, 62% mp 119-120° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.25-2.36 (2H, m), 2.83 (2H, t, J=8.2 Hz), 6.27 (1H, td, J=4.8 Hz, 9.7Hz), 7.19 (1H, t, J=7.6 Hz), 7.32 (1H, d, J=7.4 Hz), 7.49 (1H, td, J=1.6Hz, 10.0 Hz), 7.87 (1H, dd, J=1.3 Hz, 7.9 Hz), 11.60 (1H, br s);

3)N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-5,6-dihydronaphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(0.203 g, 0.562 mmol), 5,6-dihydronaphthalene-1-carboxylic acid (98 mg,0.56 mmol) and 1-hydroxybenzotriazole hydrate (86 mg, 0.56 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.11 g, 0.56 mmol) was added and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solution,dried over anhydrous magnesium sulfate and passed through silica gel.The solvent was evaporated under reduced pressure. The obtained residuewas crystallized from diisopropyl ether-hexane to give the objectivesubstance.

white crystal yield. 0.242 g, 83% mp 165-166° C.; ¹H-NMR (CDCl₃, 200MHz) δ 2.18-2.28 (2H, m), 2.70-2.85 (3H, m), 3.01 (1H, dd, J=4.5 Hz,14.3 Hz), 3.57 (1H, d, J=3.6 Hz), 4.59-4.73 (1H, m), 5.04, (1H, t, J=3.8Hz), 5.67 (1H, d, J=8.2 Hz), 5.89 (1H, tt, J=2.8 Hz, 53.1 Hz), 6.00 (1H,td, J=9.3 Hz, 9.4 Hz), 6.34 (1H, d, J=10.0 Hz), 6.85 (1H, d, J=6.6 Hz),6.99-7.14 (7H, m), 7.31 (1H, t, J=7.6 Hz), 7.43 (2H, dd, J=5.4 Hz, 8.8Hz); IR (KBr) 3266, 1640, 1514, 1209, 1123 cm⁻¹; Anal. Calcd forC₂₈H₂₄F₅NO₃: C, 64.99; H, 4.67; N, 2.71. Found: C, 65.05; H, 4.66; N,2.75.

Example 124N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(0.259 g, 0.717 mmol),6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-1-carboxylic acid (0.14 g,0.72 mmol) and 1-hydroxybenzotriazole hydrate (0.11 g, 0.72 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.14 g, 0.72 mmol) was added and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solution,dried over anhydrous magnesium sulfate and passed through silica gel.The solvent was evaporated under reduced pressure. The obtained residuewas crystallized from diisopropyl ether-hexane to give the objectivesubstance.

white crystal yield 0.339 g, 89% mp 194-195° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.41-1.63 (4H, m), 1.71-1.80 (2H, m), 2.57-2.63 (2H, m), 2.72 (1H, dd,J=10.9 Hz, 14.5 Hz), 2.73-2.79 (2H, m), 3.03 (1H, dd, J=3.8 Hz, 14.4Hz), 3.52 (1H, d, J=3.8 Hz), 4.63-4.76 (1H, m), 5.02 (1H, t, J=3.8 Hz),5.60 (1H, d, J=8.8 Hz), 5.89 (1H, tt, J=2.8 Hz, 53.1 Hz), 6.68 (1H, dd,J=1.5 Hz, 7.4 Hz), 6.93-7.14 (6H, m), 7.26-7.35 (2H, m), 7.43 (2H, dd,J=5.4 Hz, 8.6 Hz); IR (KBr) 3270, 2926, 1638, 1530, 1514, 1227, 1211,1125 cm⁻¹; Anal. Calcd for C₂₉H₂₈F₅NO₃: C, 65.28; H, 5.29; N, 2.63.Found: C, 65.23; H, 5.58; N, 2.64.

Example 1254-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(0.165 g, 0.457 mmol), 4-fluoro-1-naphthoate (87 mg, 0.46 mmol) and1-hydroxybenzotriazole hydrate (70 mg, 0.46 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (87 mg,0.46 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white crystal yield 0.198 g, 81% mp 186-187° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.89 (1H, dd, J=10.1 Hz, 14.1 Hz), 3.00 (1H, dd, J=4.8 Hz,14.4 Hz), 4.69-4.84 (1H, m), 5.00-5.06 (2H, m), 5.93 (1H, tt, J=2.9 Hz,53.1 Hz), 6.98-7.57 (13H, m), 7.75 (1H, d, J=8.0 Hz), 8.06 (1H, d, J=7.4Hz); IR (KBr) 3272, 1640, 1624, 1601, 1535, 1512, 1229, 1198, 1127, 835,760 cm⁻¹; Anal. Calcd for C₂₈H₂₁F₆NO₃: C, 63.04; H, 3.97; N, 2.63.Found: C, 63.05; H, 4.17; N, 2.49.

Example 126N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-5,6,7,8-tetrahydrobenzo[a]cyclooctene-1-carboxamide

1) 7,8,9,10-tetrahydrobenzo[a]cycloocten-5(6H)-one

To a solution of 6-phenylhexanoic acid (26.16 g, 136.1 mmol) andN,N-dimethylformamide (0.1 ml) in tetrahydrofuran (130 ml) was dropwiseadded oxalyl chloride (17.8 ml, 204 mmol) at room temperature and themixture was stirred as it was at room temperature for 0.5 hr. Thesolvent of the reaction mixture was evaporated under reduced pressure togive an acid chloride as a yellow liquid.

While stirring a suspension of aluminum chloride (36.3 g, 272 mmol) inmethylene chloride (250 ml), a solution of the acid chloride obtainedabove in methylene chloride (1.2 l) was dropwise added over 3 days. Tothe reaction solution under ice-cooling was added water to quench thereaction. The methylene chloride layer of the mixture was separated andthe aqueous layer was extracted with diethyl ether. The collectedorganic layer was dried over anhydrous magnesium sulfate and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=15/1-6/1) togive the objective substance.

pale-yellow liquid yield 16.91 g, 71% ¹H-NMR (CDCl₃, 200 MHz) δ1.47-1.59 (2H, m), 1.75-1.91 (4H, m), 2.93 (2H, t, J=6.8 Hz), 3.05 (2H,t, J=6.6 Hz), 7.16-7.44 (3H, m), 7.65 (1H, dd, J=1.5 Hz, 7.7 Hz); IR(neat) 2930, 1667, 1445, 1260, 752 cm⁻¹

2) 5,6,7,8,9,10-hexahydrobenzo[a]cycloocten-5-ol

To a solution of 7,8,9,10-tetrahydrobenzo[a]cycloocten-5(6H)-one (16.91g, 97.05 mmol) in methanol (100 ml) was added sodium borohydride (3.67g, 97.1 mmol) by small portions under ice-cooling and the mixture wasstirred at room temperature for 1 hr. The reaction solution was dilutedwith water and stirred at room temperature for 0.5 hr. The resultingprecipitate was collected and washed with water to give the objectivesubstance.

white crystal yield 16.57 g, 97% mp 79-80° C.; ¹H-NMR (CDCl₃, 200 MHz) δ0.87-1.06 (1H, m), 1.30-1.66 (5H, m), 1.85 (1H, d, J=2.8 Hz), 1.88-2.00(1H, m), 2.05-2.22 (1H, m), 2.69-2.86 (2H, m), 5.12-5.21 (1H, m),7.08-7.30 (3H, m), 7.54 (1H, dd, J=1.4 Hz, 7.4 Hz); IR (KBr) 3293, 2917,1451, 1028, 760 cm⁻¹; Anal. Calcd for C₁₂H₁₆O.0.1H₂O: C, 80.95; H, 9.17.Found: C, 80.93; H, 9.14.

3) 4-(hydroxymethyl)-5,6,7,8,9,10-hexahydrobenzo[a]cycloocten-5-ol

To a solution of 5,6,7,8,9,10-hexahydrobenzo[a]cycloocten-5-ol (16.34 g,92.70 mmol) and N,N,N′,N′-tetramethylethylenediamine (30.8 g, 204 mmol)in hexane (200 ml) was dropwise added a solution (127 ml, 204 mmol) of1.6 M n-butyllithium in hexane under ice-cooling and the mixture wasstirred overnight at 35° C. The reaction mixture was cooled to −78° C.and the crushed dry ice (40 g) was added. The reaction mixture waswarmed to room temperature under stirring. The reaction solution wasdiluted with water, acidified with conc. hydrochloric acid and washedthree times with ethyl acetate. The collected organic layer was driedover anhydrous magnesium sulfate and the solvent was evaporated underreduced pressure. The obtained crude product was passed through silicagel column chromatography (hexane/ethyl acetate=6/1) to give a crudeproduct (15.85 g) of6,7,8,9,10,10a-hexahydro-2H-cycloocta[cd][2]benzofuran-2-one as a yellowliquid.

To a suspension of lithium aluminum hydride (2.97 g, 78.4 mmol) intetrahydrofuran (150 ml) was dropwise added a solution of the liquidobtained above in tetrahydrofuran (100 ml) under ice-cooling and themixture was stirred at room temperature for 1 hr. The reaction solutionwas ice-cooled and water (3 ml), 15% aqueous sodium hydroxide solution(3 ml) and water (8 ml) were successively dropwise added thereto todecompose excess lithium aluminum hydride. The mixture was stirred as itwas at room temperature for 2 hrs. The resulting precipitate was removedby filtration and the precipitate was washed with ethyl acetate. Thesolvent of the collected filtrate was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=6/1-ethyl acetate). Crystallizationfrom diisopropyl ether gave the objective substance.

white crystal yield 11.74 g, 61% mp 137-138° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 0.66-0.85 (1H, m), 1.24-1.44 (2H, m), 1.55-1.79 (2H, m), 1.93-2.11(3H, m), 2.76-2.84 (2H, m), 2.94 (1H, s), 3.46 (1H, br s), 4.46 (1H, dd,J=8.4 Hz, 11.2 Hz), 5.02 (1H, dd, J=2.9 Hz, 11.7 Hz), 5.44 (1H, t, J=8.1Hz), 7.06-7.23 (3H, m); IR (KBr) 3220, 2922, 1449, 1053, 1009, 754 cm⁻¹;Anal. Calcd for C₁₃H₁₈O₂: C, 75.69; H, 8.80. Found: C, 75.72; H, 8.99.

4)4-[[[tert-butyl(dimethyl)silyl]oxy]methyl]-5,6,7,8,9,10-hexahydrobenzo[a]cycloocten-5-ol

To a solution of4-(hydroxymethyl)-5,6,7,8,9,10-hexahydrobenzo[a]cycloocten-5-ol (11.51g, 55.80 mmol), 4-N,N-dimethylaminopyridine (0.5 g) and triethylamine(9.33 ml, 67.0 mmol) in tetrahydrofuran (70 ml) was addedtert-butyldimethylchlorosilane (9.25 g, 61.4 mmol) at room temperatureand the mixture was stirred as it was overnight at room temperature. Thereaction solution was poured into water and extracted twice with ethylacetate. The collected organic layer was dried over anhydrous magnesiumsulfate and the solvent was evaporated under reduced pressure. Theobtained crude product was purified by silica gel column chromatography(hexane/ethyl acetate=15/1-9/1) to give the objective substance.

colorless liquid yield 17.90 g, 100% ¹H-NMR (CDCl₃, 200 MHz) δ 0.08 (3H,s), 0.14 (3H, s), 0.91 (9H, s), 1.23-1.57 (2H, m), 1.60-1.77 (2H, m),1.91-2.06 (2H, m), 2.86 (2H, t, J=4.8 Hz), 3.93 (1H, br d, J=4.8 Hz),4.79 (1H, d, J=12.4 Hz), 5.04 (1H, d, J=12.0 Hz), 5.30-5.40 (1H, m),7.07 (1H, dd, J=2.0 Hz, 7.2 Hz), 7.16 (1H, t, J=7.3 Hz), 7.23 (1H, dd,J=2.0 Hz, 7.4 Hz); IR (neat) 3412, 2928, 2855, 1472, 1462, 1254, 1073,835, 779 cm⁻¹

5) tert-butyl(5,6,7,8-tetrahydrobenzo[a]cycloocten-1-ylmethoxy)dimethylsilane

To a solution of4-[[[tert-butyl(dimethyl)silyl]oxy]methyl]-5,6,7,8,9,10-hexahydrobenzo[a]cycloocten-5-ol(17.90 g, 55.84 mmol), triethylamine (15.6 ml, 112 mmol) and4-N,N-dimethylaminopyridine (0.68 g, 5.58 mmol) in acetonitrile (100 ml)was dropwise-added a solution of methanesulfonyl chloride (9.59 g, 83.8mmol) in acetonitrile (10 ml) under ice-cooling. Lithium chloride (3.55g, 83.8 mmol) was added thereto and the mixture was stirred at roomtemperature for 6 hrs. The reaction solution was poured into water andextracted twice with ethyl acetate. The collected organic layer wasdried over anhydrous magnesium sulfate and the solvent was evaporatedunder reduced pressure. The obtained residue was dissolved inN,N-dimethylformamide (80 ml). 1,8-Diazabicyclo[5.4.0]-7-undecene (16.7ml, 112 mmol) was added and the mixture was stirred overnight at 80° C.The reaction solution was poured into water and extracted twice withethyl acetate. The collected organic layer was dried over anhydrousmagnesium sulfate and the solvent was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=15/1) to give the objectivesubstance.

colorless liquid yield 10.94 g, 65% ¹H-NMR (CDCl₃, 200 MHz) δ 0.10 (6H,s), 0.95 (9H, s), 1.37-1.49 (2H, m), 1.67 (2H, br s), 1.99-2.07 (2H, m);2.74 (2H, t, J=5.9 Hz), 4.67 (2H, s), 5.95 (1H, td, J=6.7 Hz, 11.5 Hz),6.32 (1H, d, J=11.2 Hz), 7.10 (1H, dd, J=1.3 Hz, 7.5 Hz), 7.22 (1H, t,J=7.8 Hz), 7.35 (1H, d, J=7.6 Hz); IR (neat) 2928, 2855, 1472, 1464,1254, 1111, 1078, 837, 777 cm⁻¹

6) 5,6,7,8-tetrahydrobenzo[a]cycloocten-1-ylmethanol

To a solution oftert-butyl(5,6,7,8-tetrahydrobenzo[a]cycloocten-1-ylmethoxy)dimethylsilane(10.94 g, 36.16 mmol) in tetrahydrofuran (100 ml) was added a solution(43.4 ml, 43.4 mmol) of 1.0 M tetrabutylammonium fluoride intetrahydrofuran at room temperature and the mixture was stirred at roomtemperature for 15 min. The reaction solution was poured into water andextracted twice with ethyl acetate. The collected organic layer wasdried over anhydrous magnesium sulfate and the solvent was evaporatedunder reduced pressure. The obtained crude product was purified bysilica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to givethe objective substance.

colorless liquid yield 5.499 g, 81% ¹H-NMR (CDCl₃, 200 MHz) δ 1.40-1.52(2H, m), 1.60-1.74 (3H, m), 2.00-2.11 (2H, m), 2.76 (2H, t, J=5.8 Hz),4.68 (2H, d, J=5.6 Hz), 6.03 (1H, td, J=6.7 Hz, 11.7 Hz), 6.50 (1H, d,J=11.6 Hz), 7.14-7.28 (3H, m); IR (neat) 3324, 2926, 2853, 1449, 1065,1007, 766 cm⁻¹

7) 5,6,7,8-tetrahydrobenzo[a]cyclooctene-1-carboxylic acid

To a solution of 5,6,7,8-tetrahydrobenzo[a]cycloocten-1-ylmethanol(5.419 g, 28.78 mmol) in acetone (100 ml) were dropwise added slowly asolution of chromic anhydride (7.20 g, 72.0 mmol) and conc. sulfuricacid (6 ml) dissolved in water (20 ml) under ice-cooling. Aftercompletion of the dropwise addition, the mixture was stirred at roomtemperature for 0.5 hr. The reaction solution was ice-cooled again,isopropanol (20 ml) was added, and the mixture was stirred as it was for0.5 hr. Acetone of the reaction solution was evaporated under reducedpressure. The residue was diluted with ethyl acetate, washed three timeswith water, dried over anhydrous magnesium sulfate and the solvent wasevaporated under reduced pressure. The obtained residue was crystallizedfrom ethyl acetate-hexane to give the objective substance.

white crystal yield 2.413 g, 42% mp 164-165° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.46 (2H, br s), 1.72 (2H, br s), 2.03 (2H, br s), 2.81 (2H, t, J=5.8Hz), 5.98 (1H, td, J=7.2 Hz, 11.6 Hz), 6.85 (1H, d, J=11.8 Hz), 7.29(1H, t, J=7.8 Hz), 7.45 (1H, dd, J=1.4 Hz, 7.8 Hz), 7.94 (1H, dd, J=1.4Hz, 7.8 Hz); IR (KBr) 3080-2520, 1690, 1451, 1408, 1275, 924, 770 cm⁻¹;Anal. Calcd for C₁₃H₁₄O₂: C, 77.20; H, 6.98. Found: C, 77.38; H, 7.06.

8)N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-5,6,7,8-tetrahydrobenzo[a]cyclooctene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(0.274 g, 0.758 mmol),5,6,7,8-tetrahydrobenzo[a]cyclooctene-1-carboxylic acid (0.15 g, 0.76mmol) and 1-hydroxybenzotriazole hydrate (0.12 g, 0.76 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.15 g, 0.76 mmol) was added and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solution,dried over anhydrous magnesium sulfate and passed through silica gel.The solvent was evaporated under reduced pressure. The obtained residuewas crystallized from diisopropyl ether-hexane to give the objectivesubstance.

white powder yield 0.365 g, 86% mp 189-190° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.34-1.49 (2H, m), 1.53-1.73 (2H, m), 1.95-2.06 (2H, m), 2.70 (2H, t,J=5.9 Hz), 2.77 (1H, dd, J=10.4 Hz, 14.4 Hz), 2.97 (1H, dd, J=4.2 Hz,14.4 Hz), 3.91 (1H, br s), 4.58-4.71 (1H, m), 5.04 (1H, t, J=3.7 Hz),5.80 (1H, td, J=6.8 Hz, 11.8 Hz), 5.88 (1H, tt, J=2.9 Hz, 53.0 Hz), 6.01(1H, d, J=7.8 Hz), 6.10 (1H, d, J=11.8 Hz), 7.00-7.13 (5H, m), 7.17-7.32(4H, m), 7.41 (2H, dd, J=5.5 Hz, 8.5 Hz); IR (KBr) 3272, 2928, 1640,1535, 1514, 1225, 1198, 1128, 777 cm⁻¹; Anal. Calcd for C₃₀H₂₈F₅NO₃: C,66.05; H, 5.17; N, 2.57. Found: C, 65.96; H, 5.13; N, 2.55.

Example 127N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-8-methyl-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1) methyl6-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate

To a solution of 6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one (24.99g, 156.0 mmol) and dimethyl carbonate (42.2 g, 468 mmol) intetrahydrofuran (150 ml) was added a suspension (12.5 g, 312 mmol) of60% sodium hydride in liquid paraffin at room temperature and themixture was heated under reflux for 1 hr. The reaction solution waspoured into water, acidified with 1N hydrochloric acid and extractedtwice with ethyl acetate. The collected organic layer was dried overanhydrous magnesium sulfate and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate=15/1) to give methyl5-oxo-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate as ayellow liquid.

To a solution of the liquid obtained above in tetrahydrofuran (250 ml)was added a suspension (6.86 g, 172 mmol) of 60% sodium hydride inliquid paraffin under ice-cooling and the mixture was stirred as it wasunder ice-cooling for 0.5 hr. Methyl iodide (33.2 g, 234 mmol) was addedto the mixture at 0° C. and the mixture was stirred as it was at roomtemperature for 1 hr. The reaction solution was poured into water andextracted twice with ethyl acetate. The collected organic layer wasdried over anhydrous magnesium sulfate and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=20/1-6/1) to give theobjective substance.

pale-yellow liquid yield 35.13 g, 97% ¹H-NMR (CDCl₃, 200 MHz) δ 1.49(3H, s), 1.69-2.08 (3H, m), 2.25-2.38 (1H, m), 2.70-3.00 (2H, m), 3.62(3H, s), 7.13 (1H, d, J=7.4 Hz), 7.23-7.46 (3H, m); IR (neat) 2949,1740, 1686, 1451, 1262, 1236, 1215, 963 cm⁻¹

2) 6-methyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one

A solution of methyl6-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate(35.13 g, 151.2 mmol) and conc. hydrochloric acid (50 ml) in acetic acid(100 ml) was stirred overnight at 110° C. The reaction solution wasconcentrated, diluted with water and extracted twice with ethyl acetate.The collected organic layer was dried over anhydrous magnesium sulfateand the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane/ethylacetate=6/1) to give the objective substance.

yellow liquid yield 25.36 g, 96% ¹H-NMR (CDCl₃, 200 MHz) δ 1.22 (3H, d,J=6.6 Hz), 1.51-2.15 (4H, m), 2.85-3.10 (3H, m), 7.19-7.42 (3H, m), 7.67(1H, dd, J=1.7 Hz, 7.5 Hz); IR (neat) 2932, 1686, 1597, 1448, 1223, 737cm⁻¹

3) 6-methyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol

To a solution of6-methyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one (24.93 g, 143.1mmol) in methanol (150 ml) was added sodium borohydride (5.41 g, 143mmol) by small portions under ice-cooling and the mixture was stirred atroom temperature for 1 hr. The solvent of the reaction solution wasevaporated under reduced pressure, water was added, and the mixture wasextracted twice with ethyl acetate. The collected organic layer wasdried over anhydrous magnesium sulfate and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=2/1) to give the objectivesubstance.

colorless liquid yield 25.60 g, 100% ¹H-NMR (CDCl₃, 200 MHz) δ 0.85(1.5H, d, J=7.0 Hz), 0.90 (1.5H, d, J=6.8 Hz), 1.52-2.18 (6H, m),2.59-2.73 (1H, m), 2.92-3.10 (1H, m), 4.61 (0.5H, dd, J=2.2 Hz, 6.8 Hz),4.89 (0.5H, s), 7.05-7.23 (3H, m), 7.28-7.35 (1H, m); IR (neat) 3382,2924, 1454, 1034, 747 cm⁻¹

4)4-[[[tert-butyl(dimethyl)silyl]oxy]methyl]-6-methyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol

To a solution of 6-methyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol(25.17 g, 142.8 mmol) and N,N,N′,N′-tetramethylethylenediamine (47.4 g,314 mmol) in hexane (250 ml) was dropwise added a solution (196 ml, 314mmol) of 1.6 M n-butyllithium in hexane under ice-cooling and themixture was stirred overnight at 35° C. The reaction mixture was cooledto −78° C. and the crushed dry ice (30 g) was added. The mixture waswarmed to room temperature under-stirring. The reaction solution wasdiluted with water, acidified with conc. hydrochloric acid and washedthree times with ethyl acetate. The collected organic layer was driedover anhydrous magnesium sulfate and the solvent was evaporated underreduced pressure. The obtained crude product was passed through silicagel column chromatography (hexane/ethyl acetate=6/1) to give a crudeproduct (9.06 g) of9-methyl-7,8,9,9a-tetrahydrocyclopenta[cd][2]benzofuran-2(6H)-one as ayellow liquid.

To a suspension of lithium aluminum hydride (1.70 g, 44.8 mmol) intetrahydrofuran (100 ml) was dropwise added a solution of the liquidobtained above in tetrahydrofuran (80 ml) under ice-cooling and themixture was stirred at room temperature for 1 hr. The reaction solutionwas ice-cooled and water (1.5 ml), 15% aqueous sodium hydroxide solution(1.5 ml) and water (4 ml) were successively dropwise added thereto todecompose excess aluminum lithium hydride and the mixture was stirred asit was at room temperature for 2 hrs. The resulting precipitate wasremoved by filtration and the precipitate was washed with ethyl acetate.The solvent of the collected filtrate was evaporated under reducedpressure. The obtained residue was passed through silica gel columnchromatography (hexane/ethyl acetate=6/1−1/2) to give a crude product(8.762 g) of4-(hydroxymethyl)-6-methyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-olas a colorless liquid.

To a solution of the liquid obtained above, 4-N,N-dimethylaminopyridine(0.2 g) and triethylamine (7.49 ml, 53.7 mmol) in tetrahydrofuran (100ml) was added tert-butyldimethylchlorosilane (7.42 g, 49.2 mmol) at roomtemperature and the mixture was stirred as it was overnight at roomtemperature. The reaction solution was poured into water and extractedtwice with ethyl acetate. The collected organic layer was dried overanhydrous magnesium sulfate and the solvent was evaporated under reducedpressure. The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=15/1-6/1) to give the objectivesubstance.

colorless liquid yield 14.43 g, 32% ¹H-NMR (CDCl₃, 200 MHz) δ 0.08-0.13(6H, m), 0.91-1.16 (12H, m), 1.39-2.11 (5H, m), 2.54-2.70 (2H, m),3.18-3.33 (1H, m), 4.57-5.11 (3H, m), 7.04-7.14 (3H, m); IR (neat) 3416,2955, 2928, 2857, 1472, 1462, 1256, 1070, 837, 775 cm⁻¹

5)tert-butyl(8-methyl-6,7-dihydro-5H-benzo[a]cyclohepten-1-ylmethoxy)dimethylsilane

To a solution of4-[[[tert-butyl(dimethyl)silyl]oxy]methyl]-6-methyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol(14.43 g, 45.02 mmol), triethylamine (7.53 ml, 54.0 mmol) and4-N,N-dimethylaminopyridine (0.55 g, 4.50 mmol) in acetonitrile (50 ml)was dropwise added a solution of methanesulfonyl chloride (5.67 g, 49.5mmol) in acetonitrile (10 ml) under ice-cooling. Lithium chloride (2.86g, 67.5 mmol) was added thereto and the mixture was stirred at roomtemperature for 6 hrs. The reaction solution was poured into water andextracted twice with ethyl acetate. The collected organic layer wasdried over anhydrous magnesium sulfate and the solvent was evaporatedunder reduced pressure. The obtained residue was dissolved inN,N-dimethylformamide (50 ml). 1,8-Diazabicyclo[5.4.0]-7-undecene (13.5ml, 90.0 mmol) was added and the mixture was stirred overnight at 80° C.The reaction solution was poured into water and extracted twice withethyl acetate. The collected organic layer was dried over anhydrousmagnesium sulfate and the solvent was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=50/1) to give the objectivesubstance.

colorless liquid yield 5.608 g, 41% ¹H-NMR (CDCl₃, 200 MHz) δ 0.10 (6H,s), 0.94 (9H, s), 1.92-2.17 (4H, m), 2.00 (3H, s), 2.60 (2H, t, J=6.4Hz), 4.70 (2H, s), 6.32 (1H, s), 7.04-7.15 (2H, m), 7.32 (1H, d, J=7.8Hz); IR (neat) 2928, 2857, 1254, 1109, 1078, 835, 775 cm⁻¹

6) 8-methyl-6,7-dihydro-5H-benzo[a]cyclohepten-1-ylmethanol

To a solution oftert-butyl(8-methyl-6,7-dihydro-5H-benzo[a]cyclohepten-1-ylmethoxy)dimethylsilane(5.594 g, 18.49 mmol) in tetrahydrofuran (50 ml) was added a solution(22.2 ml, 22.2 mmol) of 1.0 M tetrabutylammonium fluoride intetrahydrofuran at room temperature and the mixture was stirred at roomtemperature for 15 min. The reaction solution was poured into water andextracted twice with ethyl acetate. The collected organic layer wasdried over anhydrous magnesium sulfate and the solvent was evaporatedunder reduced pressure. The obtained crude product was purified bysilica gel column chromatography (hexane/ethyl acetate=6/1) to give theobjective substance.

colorless liquid yield 3.000 g, 86% ¹H-NMR (CDCl₃, 200 MHz) δ 1.59 (1H,t, J=6.0 Hz), 1.99-2.19 (4H, m), 2.01 (3H, d, J=1.6 Hz), 2.62 (2H, t,J=6.4 Hz), 4.69 (2H, d, J=5.8 Hz), 6.47 (1H, d, J=1.6 Hz), 7.11-7.24(3H, m); IR (neat) 3333, 2928, 1454, 1019, 791 cm⁻¹

7) 8-methyl-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid

To a solution of8-methyl-6,7-dihydro-5H-benzo[a]cyclohepten-1-ylmethanol (2.939 g, 15.61mmol) in acetone (50 ml) was dropwise added slowly a solution of chromicanhydride (3.90 g, 39.0 mmol) and conc. sulfuric acid (3 ml) in water(10 ml) under ice-cooling. After completion of the dropwise addition,the mixture was stirred at room temperature for 0.5 hr. The reactionsolution was ice-cooled again, isopropanol (10 ml) was added, and themixture was stirred as it was for 0.5 hr. Acetone of the reactionsolution was evaporated under reduced pressure. The residue was dilutedwith ethyl acetate, washed three times with water three times, driedover anhydrous magnesium sulfate and the solvent was evaporated underreduced pressure. The obtained residue was crystallized from ethylacetate-hexane to give the objective substance.

white crystal yield 1.086 g, 34% mp 139-140° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.96-2.21 (4H, m), 2.05 (3H, d, J=1.4 Hz), 2.63 (2H, t, J=6.6 Hz),6.90 (1H, d, J=1.2 Hz), 7.191 (1H, t, J=7.7 Hz), 7.38 (1H, d, J=7.8 Hz),7.90 (1H, dd, J=1.3 Hz, 7.9 Hz); IR (KBr) 3055-2530, 1682, 1449, 1310,1298, 1277, 1262 cm⁻¹; Anal. Calcd for C₁₃H₁₄O₂: C, 77.20; H, 6.98.Found: C, 77.25; H, 7.00.

8)N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-8-methyl-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(0.272 g, 0.753 mmol),8-methyl-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (0.15 g,0.75 mmol) and 1-hydroxybenzotriazole hydrate (0.12 g, 0.75 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.14 g, 0.75 mmol) was added and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solution,dried over anhydrous magnesium sulfate and passed through silica gel.The solvent was evaporated under reduced pressure. The obtained residuewas crystallized from diisopropyl ether-hexane to give the objectivesubstance.

white crystal yield 0.365 g, 89% mp 149-150° C.; ¹H-NMR. (CDCl₃, 200MHz) δ 1.86 (3H, s), 1.96-2.14 (4H, m), 2.58 (2H, t, J=6.1 Hz), 2.78(1H, dd, J=10.1 Hz, 14.5 Hz), 2.97 (1H, dd, J=4.6 Hz, 14.4 Hz), 3.93(1H, br s), 4.57-4.70 (1H, m), 5.03 (1H, s), 5.87 (1H, tt, J=3.0 Hz,52.9 Hz), 5.89 (1H, s), 6.14 (1H, s), 6.99-7.33 (9H, m), 7.42 (2H, dd,J=5.4 Hz, 8.4 Hz); IR (KBr) 3266, 2938, 1638, 1512, 1198, 1128 cm⁻¹;Anal. Calcd for C₃₀H₂₈F₅NO₃: C, 66.05; H, 5.17; N, 2.57. Found: C,66.02; H, 5.28; N, 2.57.

Example 128N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-3,4-dihydro-2H-1,5-benzodioxepine-6-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(0.221 g, 0.612 mmol), 3,4-dihydro-2H-1,5-benzodioxepine-6-carboxylicacid (0.12 g, 0.61 mmol) and 1-hydroxybenzotriazole hydrate (94 mg, 0.61mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.12 g,0.61 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white crystal yield 0.261 g, 79% mp 147-148° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.04-2.17 (2H, m), 2.82 (1H, dd, J=9.9 Hz, 14.7 Hz), 2.95 (1H, dd,J=5.0 Hz, 15.0 Hz), 3.84 (2H, t, J=5.7 Hz), 4.05-4.22 (2H, m), 4.27 (1H,d, J=4.2 Hz), 4.58-4.70 (1H, m), 5.09 (1H, t, J=3.1 Hz), 5.86 (1H, tt,J=2.8 Hz, 53.0 Hz), 6.97-7.13 (7H, m), 7.26 (1H, t, J=7.9 Hz), 7.42 (2H,dd, J=5.2 Hz, 8.6 Hz), 7.77 (1H, dd, J=2.1 Hz, 7.5 Hz), 7.94 (1H, br d,J=7.0 Hz); IR (KBr) 3283, 1636, 1547, 1512, 1304, 1264, 1229, 1204,1125, 1044 cm⁻¹; Anal. Calcd for C₂₇H₂₄F₅NO₅: C, 60.34; H, 4.50; N,2.61. Found: C, 60.43; H, 4.46; N, 2.82.

Example 129 ethylN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]carbamate

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(1.604 g, 4.439 mmol) and sodium hydrogen carbonate (0.75 g, 8.88 mmol)in tetrahydrofuran (30 ml), ethyl chlorocarbonate (0.47 ml, 4.88 mmol)was added and the mixture was stirred overnight, at room temperature.The reaction solution was diluted with ethyl acetate, washed withaqueous sodium hydrogen carbonate solution, dried over anhydrousmagnesium sulfate and passed through silica gel. The solvent wasevaporated under reduced pressure. The obtained residue was crystallizedfrom diisopropyl ether-hexane to give the objective substance.

white crystal yield 1.696 g, 88% mp 113-114° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.16 (3H, t, J=6.9 Hz), 2.68 (1H, dd, J=9.8 Hz, 14.6 Hz), 2.80 (1H,dd, J=5.2 Hz, 14.6 Hz), 3.01 (1H, br s), 3.95-4.17 (3H, m), 4.71 (1H, d,J=8.8 Hz), 4.93 (1H, s), 5.89 (1H, tt, J=2.9 Hz, 53.1 Hz), 6.95-7.14(5H, m), 7.27 (1H, t, J=7.9 Hz), 7.38 (2H, dd, J=5.3 Hz, 8.7 Hz); IR(KBr) 3333, 1686, 1541, 1231, 1206, 1132 cm⁻¹; Anal. Calcd forC₂₀H₂₀F₅NO₄: C, 55.43; H, 4.65; N, 3.23. Found: C, 55.65; H, 4.41; N,3.15.

Example 130 tert-butylN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]carbamate

(1RS,2SR)-2-Amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(2.085 g, 5.771 mmol) and di-tert-butyl dicarbonate (1.51 g, 6.92 mmol)were stirred in tetrahydrofuran (50 ml) at room temperature for 1 hr.The solvent of the reaction solution was evaporated under reducedpressure and the obtained residue was crystallized from hexane to givethe objective substance.

white crystal yield 2.555 g, 96% mp 145-146° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.35 (9H, s), 2.63-2.85 (2H, m), 3.25 (1H, br s), 4.00-4.12 (1H, m),4.56 (1H, br d, J=8.8 Hz), 4.92 (1H, br s), 5.89 (1H, tt, J=2.8 Hz, 53.1Hz), 6.97-7.11 (5H, m), 7.27 (1H, t, J=7.8 Hz), 7.38 (2H, dd, J=5.4 Hz,8.4 Hz); IR (KBr) 3357, 1682, 1532, 1211, 1123 cm⁻¹; Anal. Calcd forC₂₂H₂₄F₅NO₄: C, 57.27; H, 5.24; N, 3.04. Found: C, 57.29; H, 5.20; N,2.96.

Example 1314-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]naphthalene-1-carboxamide

1) ethyl3-(4-fluorophenyl)-3-oxo-2-[4-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate

A solution of 4-(1,1,2,2-tetrafluoroethoxy)toluene (6.73 g, 32.3 mmol),N-bromosuccinimide (5.75 g, 32.3 mmol) and 2,2-azobis(isobutyronitrile)(0.2 g) in carbon tetrachloride (30 ml) was heated under reflux for 0.5hr. After cooling the reaction solution to room temperature, the whiteprecipitate as removed by filtration and the precipitate was washed withdiethyl ether. The solvent of the collected filtrate was evaporatedunder reduced pressure to give a crude product of4-(1,1,2,2-tetrafluoroethoxy)benzyl bromide as a pale-yellow liquid.

To a solution of ethyl (4-fluorobenzoyl)acetate (6.177 g, 29.39 mmol) in1,2-dimethoxyethane (50 ml) was added a suspension (1.18 g, 29.4 mmol)of 60% sodium hydride in liquid paraffin under ice-cooling and themixture was stirred as it was for 0.5 hr. A solution of4-(1,1,2,2-tetrafluoroethoxy)benzyl bromide obtained above in1,2-dimethoxyethane (10 ml) was added thereto at room temperature andthe mixture was stirred at room temperature for 8 hrs. The reactionsolution was poured into water and extracted twice with ethyl acetate.The collected organic layer was dried over anhydrous magnesium sulfateand the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography-(hexane/ethylacetate=15/1-9/1) and crystallized from hexane to give the objectivesubstance.

white crystal yield 8.228 g, 67% mp 67-68° C.; ¹H-NMR (CDCl₃, 200 MHz) δ1.11 (3H, t, J=7.1 Hz), 3.32 (2H, d, J=7.4 Hz), 4.10 (2H, q, J=7 1 Hz),4.55 (1H, t, J=7.3 Hz), 5.88 (1H, tt, J=2.9 Hz, 53.1 Hz), 7.08-7.26 (6H,m), 7.98 (2H, dd, J=5.3 Hz, 8.9 Hz); IR (KBr) 1725, 1676, 1599, 1512,1304, 1281, 1242, 1215, 1202, 1186, 1155, 1115, 1098, 843 cm⁻¹; Anal.Calcd for C₂₀H₁₇F₅O₄: C, 57.70; H, 4.12. Found: C, 57.70; H, 4.22.

2) ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[4-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate

While stirring zinc chloride (5.15 g, 37.8 mmol) in diethyl ether (80ml), sodium borohydride (2.86 g, 75.6 mmol) was added as it was at roomtemperature and the mixture was stirred as it was for 2 hrs. Theinsoluble material of the mixture was removed by filtration and washedwith diethyl ether to give a solution of zinc borohydride in diethylether. To the obtained solution was added a solution of ethyl3-(4-fluorophenyl)-3-oxo-2-[4-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate(7.865 g, 18.89 mmol) in diethyl ether (30 ml) at room temperature andthe mixture was stirred as it was for 2 hrs. Dilute hydrochloric acidwas added to the reaction solution by small portions to decompose excesszinc borohydride. The mixture was extracted twice with ethyl acetate.The collected organic layer was dried over anhydrous magnesium sulfateand the solvent was evaporated under reduced pressure. The obtainedcrude product was purified by silica gel column chromatography(hexane/ethyl acetate=6/1−3/1) to give the objective substance.

colorless liquid yield 7.687 g, 97% ¹H-NMR (CDCl₃, 200 MHz) δ 0.91 (3H,t, J=7.2 Hz), 2.88-3.03 (4H, m), 3.88 (2H, dq, J=1.7 Hz, 7.1 Hz), 5.02(1H, t, J=3.3 Hz), 5.88 (1H, tt, J=2.9 Hz, 53.1 Hz), 7.05 (2H, t, J=8.8Hz), 7.08 (4H, s), 7.37 (2H, dd, J=5.6 Hz, 8.8 Hz); IR (neat) 3468,1725, 1508, 1306, 1277, 1190, 1159, 1123, 837 cm⁻¹

3)(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[4-(1,1,2,2-tetrafluoroethoxy)benzyl]propionicacid

To a solution of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[4-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate(7.556 g, 18.06 mmol) in methanol (30 ml)—tetrahydrofuran (30 ml) wasadded 1N aqueous sodium hydroxide solution (36.1 ml, 36.1 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas concentrated, diluted with water, acidified with 1N hydrochloricacid and extracted twice with ethyl acetate. The collected organic layerwas dried over anhydrous sodium sulfate and the solvent was evaporatedunder reduced pressure. The residue was crystallized from hexane to givethe objective substance.

white crystal yield 6.260 g, 89% mp 128-129° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.91-3.07 (3H, m), 5.05 (1H, s), 5.88 (1H, tt, J=2.8 Hz, 53.1 Hz),7.04 (2H, t, J=8.6 Hz), 7.07 (4H, s), 7.35 (2H, dd, J=5.3 Hz, 8.5 Hz);IR (KBr) 3630, 3200-2480, 1698, 1512, 1283, 1233, 1190, 1128, 1100, 839cm⁻¹; Anal. Calcd for C₁₈H₁₅F₅O₄: C, 55.39; H, 3.87. Found: C, 55.42; H,3.71.

4)(4RS,5SR)-5-(4-fluorophenyl)-4-[4-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[4-(1,1,2,2-tetrafluoroethoxy)benzyl]propionicacid (5.072 g, 12.99 mmol) in tetrahydrofuran (40 ml) were addedtriethylamine (2.72 ml, 19.5 mmol) and diphenylphosphoryl azide (3.93 g,14.3 mmol) and the mixture was heated under reflux overnight. Thesolvent of the reaction solution was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1) and crystallized fromdiethyl ether-hexane to give the objective substance.

white crystal yield 4.673 g, 93% mp 154-155° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.18-2.35 (2H, m), 4.24 (1H, dt, J=5.4 Hz, 8.7 Hz), 5.05 (1H, br s),5.80 (1H, d, J=8.0 Hz), 5.90 (1H, tt, J=2.8 Hz, 53.1 Hz), 7.05 (2H, t,J=8.4 Hz), 7.14 (2H, d, J=8.8 Hz), 7.15 (2H, d, J=8.6 Hz), 7.36 (2H, dd,J=5.2 Hz, 8.6 Hz); IR (KBr) 3258, 1736, 1510, 1231, 1213, 1192, 1128,1105 cm⁻¹; Anal. Calcd for C₁₈H₁₄F₅NO₃: C, 55.82; H, 3.64; N, 3.62.Found: C, 55.89; H, 3.63; N, 3.44.

5)(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol

(4RS,5SR)-5-(4-Fluorophenyl)-4-[4-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one(4.485 g, 11.58 mmol) and sodium hydroxide (1.85 g, 46.3 mmol) wereheated under reflux in ethanol (30 ml)—water (2 ml) for 6 hrs. Thereaction solution was diluted with water and extracted twice with ethylacetate. The collected organic layer was dried over anhydrous sodiumsulfate and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel (APS type) column chromatography(hexane/ethyl acetate=3/1-ethyl acetate) and crystallized fromdiisopropyl ether-hexane to give the objective substance.

white crystal yield 3.447 g, 82% mp 78-79° C.; ¹H-NMR (CDCl₃, 200 MHz) 62.36 (1H, dd, J=10.5 Hz, 13.7 Hz), 2.80 (1H, dd, J=3.0 Hz, 13.8 Hz),3.26 (1H, ddd, J=3.5 Hz, 4.9 Hz, 10.2 Hz), 4.65 (1H, d, J=4.8 Hz), 5.90(1H, tt, J=3.0 Hz, 53.1 Hz), 7.08 (2H, t, J=8.6 Hz), 7.14 (4H, s), 7.37(2H, dd, J=5.6 Hz, 8.4 Hz); IR (KBr) 3360, 2740, 1508, 1275, 1231, 1215,1192, 1119, 1096, 1040, 856 cm⁻¹; Anal. Calcd for C₁₇H₁₆F₅NO₂: C, 56.51;H, 4.46; N, 3.88. Found: C, 56.52; H, 4.41; N, 3.66.

6)4-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(0.163 g, 0.451 mmol), 4-fluoro-1-naphthoate (86 mg, 0.45 mmol) and1-hydroxybenzotriazole hydrate (69 mg, 0.45 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg,0.45 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white crystal yield 0.212 g, 88% mp 192-193° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.87 (1H, dd, J=10.4 Hz, 14.4 Hz), 2.97 (1H, dd, J=4.8 Hz,13.8 Hz), 4.68-4.82 (1H, m), 5.01-5.08 (2H, m), 5.94 (1H, tt, J=2.9 Hz,53.1 Hz), 6.99-7.12 (6H, m), 7.19-7.26 (3H, m), 7.41-7.58 (4H, m), 7.73(1H, d, J=8.2 Hz), 8.07 (1H, d, J=7.8 Hz); IR (KBr) 3285, 1644, 1628,1601, 1535, 1508, 1314, 1264, 1233, 1200, 1127, 1113, 1094, 837 cm⁻¹;Anal. Calcd for C₂₈H₂₁F₆NO₃: C, 63.04; H, 3.97; N, 2.63. Found: C,62.98; H, 3.86; N, 2.60.

Example 1324-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(trifluoromethoxy)benzyl]ethyl]naphthalene-1-carboxamide

1) ethyl3-(4-fluorophenyl)-3-oxo-2-[3-(trifluoromethoxy)benzyl]propionate

To a solution of ethyl (4-fluorobenzoyl)acetate (4.530 g, 21.55 mmol) in1,2-dimethoxyethane (50 ml) was added a suspension (0.86 g, 21.6 mmol)of 60% sodium hydride in liquid paraffin under ice-cooling and themixture was stirred as it was for 0.5 hr. A solution of3-(trifluoromethoxy)benzyl bromide (5.50 g, 21.6 mmol) in1,2-dimethoxyethane (10 ml) was added at room temperature and themixture was stirred at room temperature for 8 hrs. The reaction solutionwas poured into water and extracted twice with ethyl acetate. Thecollected organic layer was dried over anhydrous magnesium-sulfate andthe solvent was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (hexane/ethylacetate=15/1-9/1) and crystallized from hexane to give the objectivesubstance.

white crystal yield 6.824 g, 82% mp 56-57° C.; ¹H-NMR (CDCl₃, 200 MHz) δ1.12 (3H, t, J=7.1 Hz), 3.34 (2H, d, J=7.6 Hz), 4.10 (2H, q, J=7.1 Hz),4.55 (1H, t, J=7.6 Hz), 7.03-7.16 (5H, m), 7.28 (1H, dt, J=0.7 Hz, 7.7Hz), 7.98 (2H, dd, J=5.3 Hz, 8.9 Hz); IR (KBr) 1717, 1686, 1599, 1271,1258, 1236, 1217, 1177, 1152 cm⁻¹; Anal. Calcd for C₁₉H₁₆F₄O₄: C, 59.38;H, 4.20. Found: C, 59.33; H, 4.38.

2) ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(trifluoromethoxy)benzyl]propionate

While stirring zinc chloride (4.65 g, 34.1 mmol) in diethyl ether (50ml), sodium borohydride (2.58 g, 68.3 mmol) was added as it was and themixture was stirred as it was for 2 hrs. The insoluble material of themixture was removed by filtration and washed with diethyl ether to givea solution of zinc borohydride in diethyl ether. To the obtainedsolution was added a solution of ethyl3-(4-fluorophenyl)-3-oxo-2-[3-(trifluoromethoxy)benzyl]propionate (6.559g, 17.07 mmol) in diethyl ether (30 ml) at room temperature and themixture was stirred as it was for 2 hrs. Dilute hydrochloric acid wasadded to the solution by small portions to decompose excess zincborohydride. The mixture was extracted twice with ethyl acetate. Thecollected organic layer was dried over anhydrous magnesium sulfate andthe solvent was evaporated under reduced pressure. The obtained crudeproduct was purified by silica gel column chromatography (hexane/ethylacetate=6/1−3/1) to give the objective substance.

colorless liquid yield 6.574 g, 100%. ¹H-NMR (CDCl₃, 200 MHz) δ 0.93(3H, t, J=7.1 Hz), 2.89 (1H, d, J=2.8 Hz), 2.91-3.07 (3H, m), 3.88 (2H,q, J=7.2 Hz), 5.02 (1H, t, J=3.6 Hz), 6.95-7.11 (5H, m), 7.25 (1H, t,J=7.9 Hz), 7.37 (2H, dd, J=5.2 Hz, 8.4 Hz); IR (neat) 3445, 1728, 1715,1512, 1260, 1219, 1161, 839 cm⁻¹

3)(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(trifluoromethoxy)benzyl]propionicacid

To a solution of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(trifluoromethoxy)benzyl]propionate(6.391 g, 16.54 mmol) in methanol (30 ml)—tetrahydrofuran (20 ml) wasadded 1N aqueous sodium hydroxide solution (33.1 ml, 33.1 mol) and themixture was stirred overnight at room temperature. The reaction solutionwas concentrated, diluted with water, acidified with 1N hydrochloricacid and extracted twice with ethyl acetate. The collected organic layerwas dried over anhydrous sodium sulfate and the solvent was evaporatedunder reduced pressure. The residue was crystallized from hexane to givethe objective substance.

white crystal yield 5.055 g, 85% mp 108-110° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.90-3.10 (3H, m), 5.06 (1H, s), 6.95-7.11 (5H, m), 7.25 (1H, t, J=7.9Hz), 7.36 (2H, dd, J=5.6 Hz, 8.8 Hz); IR (KBr) 3343, 3020-2550, 1694,1516, 1283, 1258, 1238, 1225, 1165, 837 cm⁻¹; Anal. Calcd forC₁₇H₁₄F₄O₄: C, 56.99; H, 3.94. Found: C, 56.98; H, 3.85.

4)(4RS,5SR)-5-(4-fluorophenyl)-4-[3-(trifluoromethoxy)benzyl]-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(trifluoromethoxy)benzyl]propionicacid (4.649 g, 12.98 mmol) in tetrahydrofuran (50 ml) were addedtriethylamine (2.71 ml, 19.5 mmol) and diphenylphosphoryl azide (3.93 g,14.3 mmol) and the mixture was heated under reflux overnight. Thesolvent of the reaction solution was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1) and crystallized fromdiethyl ether-hexane to give the objective substance.

white crystal yield 4.330 g, 94% mp 145-146° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.21-2.37 (2H, m), 4.26 (1H, dt, J=6.1 Hz, 8.3 Hz), 5.11 (1H, br s),5.80 (1H, d, J=8.0 Hz), 6.87 (1H, s), 6.96 (1H, d, J=7.2 Hz), 7.09-7.19(3H, m), 7.28 7.39 (3H, m); IR (KBr) 3248, 1736, 1516, 1256, 1227, 1163cm⁻¹; Anal. Calcd for C₁₇H₁₃F₄NO₃: C, 57.47; H, 3.69; N, 3.94. Found: C,57.54; H, 3.73; N, 4.01

5)(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(trifluoromethoxy)phenyl]propan-1-ol

(4RS,5SR)-5-(4-Fluorophenyl)-4-[3-(trifluoromethoxy)benzyl]-1,3-oxazolidin-2-one(4.071 g, 11.46 mmol) and sodium hydroxide (1.83 g, 45.8 mmol) wereheated under reflux in ethanol (30 ml)—water (2 ml) for 6 hrs. Thereaction solution was diluted with water and extracted twice with ethylacetate. The collected organic layer was dried over anhydrous sodiumsulfate and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel (APS type) column chromatography(hexane/ethyl acetate=3/1-ethyl acetate) to give the objectivesubstance.

pale-yellow liquid yield 3.722 g, 99% ¹H-NMR (CDCl₃, 200 MHz) δ 2.38(1H, dd, J=10.3 Hz, 13.9 Hz) 2.82 (1H, dd, J=3.3 Hz, 13.9 Hz), 3.27 (1H,ddd, 3.4 Hz, 4.8 Hz, 10.3 Hz), 4.65 (1H, d, J=5.0 Hz), 7.01-7.13 (5H,m), 7.27-7.42 (3H, m); IR (neat) 2260-2860, 1508, 1260, 1217, 1159 cm⁻¹

6)4-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(trifluoromethoxy)benzyl]ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(trifluoromethoxy)phenyl]propan-1-ol(0.247 g, 0.750 mmol), 4-fluoro-1-naphthoate (0.14 g, 0.75 mmol) and1-hydroxybenzotriazole hydrate (0.11 g, 0.75 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.14g, 0.75 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white crystal yield 0.262 g, 70% mp 189-190° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.90 (1H, dd, J=10.7 Hz, 14.3 Hz), 3.04 (1H, dd, J=4.3 Hz,14.1 Hz), 4.67-4.81 (1H, m), 5.00 (1H, t, J=4.0 Hz), 5.21 (1H, d, J=3.6Hz), 6.99-7.34 (8H, m), 7.39-7.57 (5H, m), 7.69 (1H, d, J=8.0 Hz), 8.06(1H, d, J=7.2 Hz); IR (KBr) 3268, 1642, 1624, 1601, 1537, 1512, 1269,1227, 1173, 835, 760 cm⁻¹; Anal. Calcd for C₂₇H₂₀F₅NO₃: C, 64.67; H,4.02; N, 2.79. Found: C, 64.58; H, 4.05; N, 2.59.

Example 133N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(trifluoromethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(trifluoromethoxy)phenyl]propan-1-ol(0.239 g, 0.726 mmol), 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylicacid (0.14 g, 0.73 mmol) and 1-hydroxybenzotriazole hydrate (0.11 g,0.73 mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.14 g,0.73 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white crystal yield 0.274 g, 76% mp 177-178° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 1.91-2.04 (2H, m), 2.18-2.27 (2H, m), 2.68 (2H, t, J=5.9 Hz),2.78-2.96 (2H, m), 4.60-4.74 (1H, m), 4.93 (1H, d, J=3.6 Hz), 4.98 (1H,t, J=3.7 Hz), 5.88 (1H, td, J=5.3 Hz, 11.9 Hz), 6.18 (1H, d, J=12.2 Hz),6.73 (1H, d, J=9.2 Hz), 6.92 (1H, dd, J=1.9 Hz, 7.3 Hz), 7.01-7.16 (7H,m), 7.26 (1H, d, J=8.8 Hz), 7.49 (2H, dd, J=5.5 Hz, 8.5 Hz); IR (KBr)3268, 1640, 1539, 1512, 1269, 1221, 1153 cm⁻¹; Anal. Calcd forC₂₈H₂₅F₄NO₃: C, 67.33; H, 5.04; N, 2.80. Found: C, 67.22; H, 4.98; N,2.78.

Example 1344-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethoxy)benzyl]ethyl]naphthalene-1-carboxamide

1) ethyl3-(4-fluorophenyl)-3-oxo-2-[4-(trifluoromethoxy)benzyl]propionate

To a solution of ethyl (4-fluorobenzoyl)acetate (4.140 g, 19.70 mmol) in1,2-dimethoxyethane (50 ml) was added a suspension (0.79 g, 19.7 mmol)of 60% sodium hydride in liquid paraffin under ice-cooling and themixture was stirred as it was for 0.5 hr. A solution of4-(trifluoromethoxy)benzyl bromide (5.02 g, 19.7 mmol) in1,2-dimethoxyethane (10 ml) was added at room temperature and themixture was stirred at room temperature for 8 hrs. The reaction solutionwas poured into water and extracted twice with ethyl acetate. Thecollected organic layer was dried over anhydrous magnesium sulfate andthe solvent was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (hexane/ethylacetate=15/1-9/1) and crystallized from hexane to give the objectivesubstance.

white crystal yield 5.869 g, 78% mp 53.5-54.5° C.; ¹H-NMR (CDCl₃, 200MHz) δ 1.11 (3H, t, J=7.1 Hz); 3.32 (2H, d, J=7.4 Hz), 4.10 (2H, q,J=7.1 Hz), 4.54 (1H, t, J=7.3 Hz), 7.10 (2H, d, J=8.4 Hz), 7.12 (2H, t,J=8.6 Hz), 7.25 (2H, d, J=8.8 Hz), 7.98 (2H, dd, J=5.2 Hz, 9.0 Hz); IR(KBr) 1732, 1682, 1597, 1507, 1325, 1273, 1236, 1152, 1101, 851 cm⁻¹;Anal. Calcd for C₁₉H₁₆F₄O₄: C, 59.38; H, 4.20. Found: C, 59.38; H, 4.27.

2) ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[4-(trifluoromethoxy)benzyl]propionate

While stirring zinc chloride (3.98 g, 29.2 mmol) in diethyl ether (50ml), sodium borohydride (2.21 g, 58.4 mmol) was added at roomtemperature and the mixture was stirred as it was for 2 hrs. Theinsoluble material of the mixture was removed by filtration and washedwith diethyl ether to give a solution of zinc borohydride in diethylether. To the obtained solution was added a solution of ethyl3-(4-fluorophenyl)-3-oxo-2-[4-(trifluoromethoxy)benzyl]propionate (5.610g, 14.60 mmol) in diethyl ether (30 ml) at room temperature and themixture was stirred as it was for 2 hrs. Dilute hydrochloric acid wasadded to the reaction solution by small portions to decompose excesszinc borohydride. The mixture was extracted twice with ethyl acetate.The collected organic layer was dried over anhydrous magnesium sulfateand the solvent was evaporated under reduced pressure. The obtainedcrude product was purified by silica gel column chromatography(hexane/ethyl acetate=6/1−3/1) to give the objective substance.

colorless liquid yield 5.601 g, 99% ¹H-NMR (CDCl₃, 200 MHz) δ 0.91 (3H,t, J=7.2 Hz), 2.89 (1H, d, J=2.6 Hz), 2.93-3.03 (3H, m), 3.88 (2H, dq,J=1.5 Hz, 7.2 Hz), 5.02 (1H, t, J=3.6 Hz), 7.05 (2H, t, J=8.8 Hz), 7.09(4H, s), 7.37 (2H, dd, J=5.6 Hz, 8.4 Hz); IR (neat) 3445, 1728, 1715,1510, 1264, 1225, 1161, 839 cm⁻¹

3)(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[4-(trifluoromethoxy)benzyl]propionicacid

To a solution of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[4-(trifluoromethoxy)benzyl]propionate(5.440 g, 14.08 mmol) in methanol (30 ml)—tetrahydrofuran (20 ml) wasadded 1N aqueous sodium hydroxide solution (28.2 ml, 28.2 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas concentrated, diluted with water, acidified with 1N hydrochloricacid and extracted twice with ethyl acetate. The collected organic layerwas dried over anhydrous sodium sulfate and the solvent was evaporatedunder reduced pressure. The residue was crystallized from hexane to givethe objective substance.

white crystal yield 4.071 g, 80% mp 111-112° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.90-3.10 (3H, m), 5.05-5.08 (1H, m), 7.05 (2H, t, J=8.4 Hz), 7.08(4H, s), 7.36 (2H, dd, J=5.6 Hz, 8.8 Hz); IR (KBr) 3343, 3100-2550,1692, 1514, 1285, 1208, 1163, 839 cm⁻¹; Anal. Calcd for C₁₇H₁₄F₄O₄: C,56.99; H, 3.94. Found: C, 56.97; H, 4.05.

4)(4RS,5SR)-5-(4-fluorophenyl)-4-[4-(trifluoromethoxy)benzyl]-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[4-(trifluoromethoxy)benzyl]propionicacid (3.637 g, 10.15 mmol) in tetrahydrofuran (50 ml) were addedtriethylamine (2.12 ml, 15.2 mmol) and diphenylphosphoryl azide (3.07 g,11.2 mmol) and the mixture was heated under reflux overnight. Thesolvent of the reaction solution was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography. (hexane/ethyl acetate=3/1-1/1) and crystallized fromdiethyl ether-hexane to give the objective substance.

white crystal yield 3.340 g, 93% mp 163-164° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.19-2.35 (2H, m), 4.17-4.29 (1H, m), 4.96 (1H, br s), 5.80 (1H, d,J=8.2 Hz), 7.02-7.17 (6H, m), 7.36 (2H, dd, J=5.2 Hz, 9.0 Hz); IR (KBr)3243, 1736, 1510, 1275, 1236, 1150 cm⁻¹; Anal. Calcd for C₁₇H₁₃F₄NO₃: C,57.47; H, 3.69; N, 3.94. Found: C, 57.48; H, 3.58; N, 4.04.

5)(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethoxy)phenyl]propan-1-ol

(4RS,5SR)-5-(4-Fluorophenyl)-4-[4-(trifluoromethoxy)benzyl]-1,3-oxazolidin-2-one(3.057 g, 8.604 mmol) and sodium hydroxide (1.38 g, 34.4 mmol) washeated under reflux in ethanol (30 ml)—water (1.5 ml) for 6 hrs. Thereaction solution was diluted with water and extracted twice with ethylacetate. The collected organic layer was dried over anhydrous sodiumsulfate and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel (APS type) column chromatography(hexane/ethyl acetate=3/1-ethyl acetate) and crystallized fromdiisopropyl ether-hexane to give the objective substance.

white crystal yield 2.406 g, 85% mp 84-85° C.; ¹H-NMR (CDCl₃, 200 MHz) δ2.36 (1H, dd, J=10.3 Hz, 13.9 Hz), 2.81 (1H, dd, J=3.3 Hz, 13.5 Hz),3.26 (1H, ddd, J=3.3 Hz, 4.8 Hz, 10.3 Hz), 4.65 (1H, d, J=4.8 Hz), 7.07(2H, t, J=8.8 Hz), 7.15 (4H, s), 7.37 (2H, dd, J=5.2 Hz, 8.4 Hz); IR(KBr) 3350-2750, 1598, 1277, 1217, 1194, 1165, 1047 cm⁻¹; Anal. Calcdfor C₁₆H₁₅F₄NO₂: C, 58.36; H, 4.59; N, 4.25. Found: C, 58.43; H, 4.54;N, 4.31.

6)4-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethoxy)benzyl]ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethoxy)phenyl]propan-1-ol(0.212 g, 0.644 mmol), 4-fluoro-1-naphthoate (0.12 g, 0.64 mmol) and1-hydroxybenzotriazole hydrate (0.10 g, 0.64 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.12g, 0.64 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from ethyl acetate-diisopropyl ether-hexane to give theobjective substance.

white crystal yield 0.276 g, 86% mp 230-231° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.87 (1H, dd, J=10.8 Hz, 14.6 Hz), 3.00 (1H, dd, J=4.2 Hz,14.2 Hz), 4.67-4.81 (1H, m), 5.02 (1H, t, J=4.1 Hz), 5.19 (1H, d, J=3.8Hz), 6.99-7.57 (13H, m), 7.67 (1H, d, J=8.4 Hz), 8.06 (1H, d, J=8.0 Hz);IR (KBr) 3281, 1644, 1537, 1512, 1269, 1227, 1217, 1175, 835 cm⁻¹; Anal.Calcd for C₂₇H₂₀F₅NO₃: C, 64.67; H, 4.02; N, 2.79. Found: C, 64.57; H,4.02; N, 2.61.

Example 135N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethoxy)phenyl]propan-1-ol(0.238 g, 0.723 mmol), 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylicacid (0.14 g, 0.72 mmol) and 1-hydroxybenzotriazole hydrate (0.11 g,0.72 mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.14 g,0.72 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white crystal yield 0.279 g, 77% mp 202-203° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 1.91-2.04 (2H, m), 2.18-2.27 (2H, m), 2.68 (2H, t, J=5.9 Hz),2.78-2.92 (2H, m), 4.62-4.72 (1H, m), 4.96-5.02 (2H, m), 5.88 (1H, td,J=5.3 Hz, 11.7 Hz), 6.17 (1H, d, J=12.2 Hz), 6.74 (1H, d, J=10.0 Hz),6.90 (1H, dd, J=2.0 Hz, 7.6 Hz), 7.01-7.15 (6H, m), 7.22 (2H, d, J=8.8Hz), 7.50 (2H, dd, J=5.6 Hz, 8.6 Hz); IR (KBr) 3272, 1640, 1539, 1512,1269, 1229, 1202, 1159 cm⁻¹; Anal. Calcd for C₂₈H₂₅F₄NO₃: C, 67.33; H,5.04; N, 2.80. Found: C, 67.16; H, 4.94; N, 2.75.

Example 136N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((3-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

1) A mixture of ethyl 3-(4-fluorophenyl)-3-oxopropionate (10 g, 47.6mmol), 3-trifluoromethylbenzyl chloride (8.33 g, 42.8 mmol), potassiumcarbonate (13.2 g, 95.1 mmol) and acetonitrile (200 ml) was stirred at60° C. for 24 hrs. The reaction solution was concentrated under reducedpressure, water (200 ml) was added, and the mixture was extracted withethyl acetate (200, 100 ml). The extract was washed with water, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was purified by silica gel column chromatography(hexane:toluene=1:1-1:2-toluene) to give ethyl3-(4-fluorophenyl)-3-oxo-2-(3-trifluoromethylbenzyl)propionate (10.2 g,65%) as an oil.

IR ν max^(Neat)cm⁻¹: 1736, 1690, 1599, 1331, 1161, 1127, 1074. ¹H-NMR(CDCl₃)δ: 1.12 (3H, t, J=7.1 Hz), 3.38 (2H, d, J=7.4 Hz), 4.10 (2H, q,J=7.1 Hz), 4.57 (1H, t, J=7.4 Hz), 7.13 (2H, t, J=8.8 Hz), 7.35-7.60(4H, m), 7.95-8.10 (2H, m).

2) To a solution of anhydrous zinc chloride (7.4 g, 54.3 mmol) indiethyl ether (50 ml) was added sodium borohydride (4.11 g, 0.11 mol)and the mixture was stirred at room temperature for 2 hrs. The insolublematerial was removed by filtration. To the filtrate was added a solutionof ethyl 3-(4-fluorophenyl)-3-oxo-2-(3-trifluoromethylbenzyl)propionate(10 g, 27.1 mmol) in diethyl ether (20 ml) and the mixture was stirredat room temperature for 1 hr. 1N Hydrochloric acid was added to thereaction solution to terminate the reaction. The reaction solution wasextracted with ethyl acetate (100 ml). The extract was washed with waterand saturated aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=20:1-5:1) to give ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(3-trifluoromethylbenzyl)propionate(7.9 g, 79%) as a colorless oil.

IR ν max^(Neat)cm⁻¹: 1717, 1510, 1329, 1161, 1127, 1074, 839. ¹H-NMR(CDCl₃)δ: 0.92 (3H, t, J=7.2 Hz), 2.93 (1H, d, J=2.6 Hz), 2.90-3.12 (3H,m), 3.88 (2H, q, J=7.2 Hz), 5.00-5.10 (1H, m), 7.05 (2H, t, J=8.7 Hz),7.20-7.55 (6H, m).

3) To a solution of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(3-trifluoromethylbenzyl)propionate(7.9 g, 21.3 mmol) in methanol (50 ml) was added 1N aqueous sodiumhydroxide solution (42.7 ml, 42.7 mmol) and the mixture was stirred atroom temperature for 3 hrs. The reaction solution was acidified with 1Nhydrochloric acid (100 ml) and extracted with ethyl acetate (200 ml×2).The extract was washed with water, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue wascrystallized from a mixture of hexane and diethyl ether to give(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(3-trifluoromethylbenzyl)propionicacid (6.20 g, 85%).

mp 116-118° C. IR ν max^(KBr)cm⁻¹: 3424, 1717, 1678, 1514, 1325, 1238,1128, 1074, 839. elemental analysis for C₁₇H₁₄F₄O₃, Calcd: C, 59.65; H,4.12. Found: C, 59.55; H, 4.10. ¹H-NMR (DMSO-d₆)δ: 2.80-2.95 (1H, m),2.99 (1H, d, J=10.4 Hz), 3.15 (1H, d, J=10.4 Hz), 4.74 (1H, d, J=6.2Hz), 5.65-5.90 (1H, br), 7.12 (2H, t, J=8.8 Hz), 7.32-7.60 (6H, m).

4) To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(3-trifluoromethylbenzyl)propionicacid (5.85 g, 17.1 mmol) in tetrahydrofuran (100 ml) were addeddiphenylphosphoryl azide (4.78 ml, 22.2 mmol) and triethylamine (3.33ml, 23.9 mmol). The reaction solution was-heated under reflux for 4 hrs.After cooling, water (200 ml) was added, and the mixture was extractedwith ethyl acetate (200 ml). The extract was washed with 1N hydrochloricacid and saturated aqueous sodium hydrogen carbonate solution, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was purified by silica gel column chromatography(chloroform:ethyl acetate=10:1-5:1) to give(4RS,5SR)-5-(4-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(5.30 g, 91%) as crystals.

mp 177-178° C. elemental analysis for C₁₇H₁₃F₄NO₂, Calcd: C, 60.18; H,3.86; N, 4.13. Found: C, 60.20; H, 3.83; N, 4.09. ¹H-NMR (CDCl₃)δ:2.30-2.45 (2H, m), 4.20-4.40 (1H, m), 5.11 (1H, brs), 5.80 (1H, d, J=8.0Hz), 7.13 (2H, t, J=8.6 Hz), 7.15-7.60 (6H, m).

5) To a solution of(4RS,5SR)-5-(4-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(4.0 g, 11.8 mmol) in ethanol (80 ml) was added 8N aqueous sodiumhydroxide solution (7.4 ml, 59 mmol) and the mixture was heated underreflux for 4 hrs. The reaction solution was concentrated, diluted withwater (100 ml) and extracted with ethyl acetate (100 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. The residue was recrystallizedfrom ethyl acetate-hexane to give(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)-1-propanol(2.97 g, 80%).

mp 76-77° C. IR ν max^(KBr)cm⁻¹: 1605. Anal. Calcd for C₁₆H₁₅F₄NO: C,61.34; H, 4.83; N, 4.47. Found: C, 61.19; H, 4.82; N, 4.36. ¹H-NMR(CDCl₃)δ: 2.42 (1H, dd, J=13.8, 10.2 Hz), 2.89 (1H, dd, J=13.8, 3.2 Hz),3.20-3.38 (1H, m), 4.66 (1H, d, J=4.6 Hz), 7.00-7.16 (2H, m), 7.22-7.52(6H, m).

6) To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added 1-naphthoylchloride (282 ml, 1.87 mmol) and saturated aqueous sodium hydrogencarbonate (15 ml) and the mixture was stirred at room temperature for 2hrs. The reaction solution was diluted with water (100 ml) and extractedwith ethyl acetate (100 ml×2). The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was recrystallized from ethylacetate-hexane to give the title compound (582 mg, 87%).

mp 158-159° C. IR ν max^(KBr)cm⁻¹: 1638, 1622, 1534. Anal. Calcd forC₂₇H₂₁F₄NO₂: C, 69.37; H, 4.53; N, 3.00, Found: C, 69.47; H, 4.23; N,2.97. ¹H-NMR (CDCl₃)δ: 2.79 (1H, dd, J=14.4, 11.0 Hz), 2.97 (1H, dd,J=14.4, 4.0 Hz), 3.93 (1H, s), 4.70-4.90 (1H, m), 5.18 (1H, s), 5.98(1H, d, J=8.2 Hz), 6.92-7.08 (2H, m), 7.10-7.30 (3H, m), 7.32-7.80 (8H,m), 7.80-7.96 (2H, m).

Example 1374-fluoro-N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((3-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in acetonitrile (30 ml) were added4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg,1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate).Recrystallization from ethyl acetate-hexane gave the title compound (490mg, 70%).

mp 193-194° C. IR ν max^(KBr)cm⁻¹: 1642, 1626, 1601, 1514, 1329. Anal.Calcd for C₂₇H₂₀F₅NO₂: C, 66.80; H, 4.15; N, 2.89. Found: C, 66.70; H,4.11; N, 2.75. ¹H-NMR (CDCl₃)δ: 2.89 (1H, dd, J=14.2, 10.6 Hz), 3.09(1H, dd, J=14.2, 4.0 Hz), 3.34 (1H, s), 4.70-4.84 (1H, m), 5.06-5.14(1H, m), 5.98 (1H, d, J=8.8 Hz), 6.92-7.20 (4H, m), 7.40-7.60 (8H, m),7.75 (1H, d, J=8.0 Hz), 8.08 (1H, d, J=8.0 Hz).

Example 138N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((3-(trifluoromethyl)phenyl)methyl)ethyl)cyclohexanecarboxamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in ethyl acetate (15 ml) were addedcyclohexanecarbonyl chloride (288 ml, 2.15 mmol) and-saturated aqueoussodium hydrogen carbonate (15 ml) and the mixture was stirred at roomtemperature for 3 hrs. The reaction solution was diluted with water (100ml) and extracted with ethyl acetate (100 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the title compound (532 mg, 87%).

mp 190-191° C. IR ν max^(KBr)cm⁻¹: 1645, 1541, 1516, 1331. Anal. Calcdfor C₂₃H₂₅F₄NO₂: C, 65.24; H, 5.95; N, 3.31. Found: C, 65.27; H, 5.92;N, 3.21. ¹H-NMR (CDCl₃)δ: 1.00-1.38 (5H, m), 1.50-1.80 (5H, m),1.84-2.06 (1H, m), 2.78 (1H, dd, J=14.4, 10.2 Hz), 2.93 (1H, dd, J=14.4,4.4 Hz), 3.83 (1H, d, J=3.2 Hz), 4.30-4.50 (1H, m), 4.97 (1H, brs), 5.42(1H, d, J=8.4 Hz), 7.02-7.18 (2H, m), 7.24-7.54 (6H, m).

Example 139N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((3-(trifluoromethyl)phenyl)methyl)ethyl)-4-phenylbutyramide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in acetonitrile (30 ml) were added4-phenyl-n-butyric acid (236 mg, 1.44 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg,1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate).Recrystallization from ethyl acetate-hexane gave the title compound (432mg, 65%).

mp 110-111° C. IR ν max^(KBr)cm⁻¹: 1644, 1605, 1510. Anal. Calcd forC₂₆H₂₅F₄NO₂: C, 67.96; H, 5.48; N, 3.05. Found: C, 67.99; H, 5.63; N,2.96. ¹H-NMR (CDCl₃)δ: 1.66-1.90 (2H, m), 1.96-2.16 (2H, m), 2.40-2.56(2H, m), 2.68-2.96 (2H, m), 3.56 (1H, d, J=3.8 Hz), 4.32-4.50 (1H, m),4.90-5.00 (1H, m), 5.46 (1H, d, J=8.4 Hz), 7.00-7.50 (13H, m).

Example 140N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((2-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

1) A mixture of ethyl 3-(4-fluorophenyl)-3-oxopropionate (18 g, 85.7mmol), 2-trifluoromethylbenzyl chloride (15.0 g, 77.1 mmol), potassiumcarbonate (23.7 g, 0.17 mol) and acetonitrile (200 ml) was stirred at60° C. for 10 hrs. The reaction solution was concentrated under reducedpressure, water (200 ml) was added and the mixture was extracted withethyl acetate (200 ml×2). The extract was washed with water, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane:toluene=1:1) to give-ethyl3-(4-fluorophenyl)-3-oxo-2-(2-trifluoromethyl)benzylpropionate (22.3 g,71%) as an oil.

IR ν max^(Neat)cm⁻¹: 1738, 1690, 1599, 1316, 1159, 1121, 1040, 851.¹H-NMR (CDCl₃)δ: 1.11 (3H, t, J=7.2 Hz), 3.53 (2H, d, J=7.4 Hz), 4.10(2H, q, J=7.2 Hz), 4.63 (1H, t, J=7.2 Hz), 7.10 (2H, t, J=8.6 Hz),7.20-7.45 (3H, m), 7.64 (1H, d, J=7.2 Hz), 7.90-8.03 (2H, m);

2) To a solution of anhydrous zinc chloride (15.4 g, 0.113 mol) indiethyl ether (200 ml) was added sodium borohydride (9.5 g, 0.226 mol)and the mixture was stirred at room temperature for 2 hrs. The insolublematerial was removed by filtration. To the filtrate was added a solutionof ethyl 3-(4-fluorophenyl)-3-oxo-2-(2-trifluoromethyl)benzylpropionate(20.8 g, 56.5 mmol) in diethyl ether (50 ml) and the mixture was stirredat room temperature for 1 hr. 1N Hydrochloric acid was added to thereaction solution under ice-cooling to terminate the reaction. To thereaction solution were added water (200 ml) and ethyl acetate (300 ml)and extracted. The extract was washed with water and saturated aqueoussodium hydrogen carbonate solution, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=20:1-10:1) togive ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(2-trifluoromethyl)benzylpropionate(16.9 g, 82%) as a colorless oil.

IR ν max^(Neat)cm⁻¹: 1715, 1607, 1510, 1316, 1225, 1159, 1121, 1040,839. ¹H-NMR (CDCl₃)δ: 0.91 (3H, t, J=7.1 Hz), 2.98-3.30 (4H, m), 3.88(2H, q, J=7.1 Hz), 5.00-5.10 (1H, m), 7.59 (1H, d, J=7.4 Hz).

3) To a solution of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(2-trifluoromethyl)benzylpropionate(16.7 g, 45 mmol) in methanol (100 ml) was added 2N aqueous sodiumhydroxide solution (45 ml, 90.2 mmol) and the mixture was stirred atroom temperature for 4 hrs. The reaction solution was acidified with 1Nhydrochloric acid (150 ml) and extracted with ethyl acetate (150 ml×2).The extract was washed with water, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue wascrystallized from hexane to give(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(2-trifluoromethyl)benzylpropionicacid (12.6 g, 82%).

mp 158-159° C. IR ν max^(KBr)cm⁻¹: 1694, 1514, 1319, 1227, 1115, 1042,839. elemental analysis for C₁₇H₁₄F₄O₃, Calcd: C, 59.65; H, 4.12. Found:C, 59.56; H, 4.07. ¹H-NMR (DMSO-d₆)δ: 2.70-2.95 (1H, m), 2.98-3.17 (1H,m), 4.70-4.82 (1H, m), 5.70-5.85 (1H, m), 7.13 (2H, t, J=9.0 Hz),7.32-7.50 (4H, m), 7.50-7.70 (2H, m).

4) To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(2-trifluoromethyl)benzylpropionicacid (12.3 g, 35.9 mmol) in tetrahydrofuran (100 ml) were addeddiphenylphosphoryl azide (10.0 ml, 46.7 mmol) and triethylamine (7.0 ml,50.3 mmol) and the mixture was stirred for 30 min. The mixture wasfurther heated under reflux for 4 hrs and allowed to stand at roomtemperature. Water (200 ml) was added and the mixture was extracted withethyl acetate (200 ml). The extract was washed with 1N hydrochloric acidand saturated aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography(chloroform:ethyl acetate=10:1-5:1) to give(4RS,5SR)-5-(4-fluorophenyl)-4-((2-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(11.8 g, 97%) as crystals.

mp 138-140° C. IR ν max^(KBr)cm⁻¹: 1761, 1609, 1514, 1316, 1235, 1154,1115, 1063, 964, 833. elemental analysis for C₁₇H₁₃F₄NO₂ Calcd: C,60.18; H, 3.86; N, 4.13. Found: C, 60.18; H, 4.05; N, 4.06. ¹H-NMR(CDCl₃)δ: 2.20-2.40 (1H, m), 2.50-2.65 (1H, m), 4.18-4.35 (1H, m), 5.09(1H, brs), 5.84 (1H, d, J=7.6 Hz), 7.10-7.60 (7H, m), 7.66 (1H, d, J=8.4Hz).

5) To a solution of(4RS,5SR)-5-(4-fluorophenyl)-4-((2-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(10.95 g, 32.3 mmol) in ethanol (200 ml) was added 8N aqueous sodiumhydroxide solution (20 ml, 160 mmol) and the mixture was heated underreflux for 4 hrs. The reaction solution was concentrated, diluted withwater (200 ml) and extracted with ethyl, acetate (200 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. The residue was recrystallizedfrom ethyl acetate-hexane to give(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2-(trifluoromethyl)phenyl)-1-propanol(7.56 g, 75%).

mp 57-58° C. Anal. Calcd for C₁₆H₁₅F₄NO: C, 61.34; H, 4.83; N, 4.47.Found: C, 61.52; H, 4.78; N, 4.39. IR ν max^(KBr)cm⁻¹: 1607, 1508, 1316.¹H-NMR (CDCl₃)δ: 2.34-2.52 (1H, m), 2.90-3.10 (1H, m), 3.30-3.42 (1H,m), 4.74 (1H, d, J=4.4 Hz), 7.02-7.16 (2H, m), 7.20-7.52 (5H, m), 7.63(1H, d, J=7.6 Hz).

6) To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added 1-naphthoylchloride (282 ml, 1.87 mmol) and saturated aqueous sodium hydrogencarbonate (15 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (100 ml) andextracted with ethyl acetate (100 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was recrystallized from ethylacetate-hexane to give the title compound (536 mg, 80%).

mp 193-194° C. IR ν max^(KBr)cm⁻¹: 1636, 1622, 1607, 1539. Anal. Calcdfor C₂₇H₂₁F₄NO₂: C, 69.37; H, 4.53; N, 3.00. Found: C, 69.13; H, 4.37;N, 3.09. ¹H-NMR (CDCl₃)δ: 2.90-3.20 (2H, m), 3.33 (1H, d, J=3.0 Hz),4.80-5.00 (1H, m), 5.12-5.20 (1H, m), 6.07 (1H, d, J=8.8 Hz), 7.00-7.20(3H, m), 7.24-7.58 (8H, m), 7.60-7.78 (2H, m), 7.80-7.92 (2H, m).

Example 1414-fluoro-N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((2-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in acetonitrile (30 ml) were added4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg,1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=1:1).Recrystallization from ethyl acetate-hexane gave the title compound (548mg, 79%).

mp 200-201° C. IR ν max^(KBr)cm⁻¹: 1640, 1626, 1601, 1537. Anal. Calcdfor C₂₇H₂₀F₅NO₂: C, 66.80; H, 4.15; N, 2.89. Found: C, 66.67; H, 4.12;N, 2.80. ¹H-NMR (CDCl₃)δ: 2.98-3.22 (3H, m), 4.80-4.98 (1H, m),5.14-5.20 (1H, m), 6.04 (1H, d, J=8.4 Hz), 6.96-7.20 (4H, m), 7.26-7.60(7H, m), 7.65 (1H, d, J=7.8 Hz), 7.75 (1H, d, J=8.4 Hz), 8.08 (1H, d,J=8.2 Hz).

Example 142N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((2-(trifluoromethyl)phenyl)methyl)ethyl)cyclohexanecarboxamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in ethyl acetate (15 ml) were addedcyclohexanecarbonyl chloride (288 ml, 2.15 mmol) and saturated aqueoussodium hydrogen carbonate (15 ml) and the mixture was stirred at roomtemperature for 3 hrs. The reaction solution was diluted with water (100ml) and extracted with ethyl acetate (100 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the title compound (434 mg, 87%).

mp 216-217° C. IR ν max^(KBr)cm⁻¹: 1645, 1607, 1539. Anal. Calcd forC₂₃H₂₅F₄NO₂: C, 65.24; H, 5.95; N, 3.31. Found: C, 64.96; H, 5.92; N,3.19. ¹H-NMR (CDCl₃)δ: 1.00-1.30 (5H, m), 1.40-1.80 (5H, m), 1.80-2.02(1H, m), 2.80-3.02 (2H, m), 3.70 (1H, d, J=3.6 Hz), 4.40-4.60 (1H, m),4.98-5.06 (1H, m), 5.51 (1H, d, J=8.2 Hz), 7.00-7.16 (2H, m), 7.20-7.52(5H, m), 7.59 (1H, d, J=7.6 Hz).

Example 143N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((2-(trifluoromethyl)phenyl)methyl)ethyl)-4-phenylbutyramide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in acetonitrile (30 ml) were added4-phenyl-n-butyric acid (236 mg, 1.44 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg,1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2) The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:acetone=1:1).Recrystallization from ethyl acetate-hexane gave the title compound (501mg, 76%).

mp 161-162° C. IR ν max^(KBr)cm⁻¹: 1645, 1537, 1514. Anal. Calcd forC₂₆H₂₅F₄NO₂: C, 67.96; H, 5.48; N, 3.05. Found: C, 67.96; H, 5.41; N,2.94. ¹H-NMR (CDCl₃)δ: 1.64-1.84 (2H, m), 1.86-2.12 (2H, m), 2.38-2.44(2H, m), 2.91 (2H, d, J=7.2 Hz), 3.29 (1H, d, J=3.6 Hz), 4.40-4.60 (1H,m), 4.98-5.06 (1H, m), 5.51 (1H, d, J=7.6 Hz), 7.00-7.34 (9H, m),7.36-7.48 (3H, m), 7.57 (1H, d, J=7.6 Hz)

Example 144N-((1RS,2SR)-2-(4-fluorophenyl)-1-((4-fluorophenyl)methyl)-2-hydroxyethyl)-1-naphthalenecarboxamide

1) A mixture of ethyl 3-(4-fluorophenyl)-3-oxopropionate (20 g, 95.1mmol), 4-fluorobenzyl bromide (18.0 g, 85.6 mmol), potassium carbonate(26.3 g, 0.19 mol) and acetonitrile (300 ml) was stirred at 60° C. for 2hrs. The reaction solution was concentrated under reduced pressure,water (200 ml) was added, and the mixture was extracted with ethylacetate (200, 100 ml). The extract was washed with water, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography(hexane:toluene=1:1-1:5) to give ethyl2-(4-fluorobenzyl)-3-(4-fluorophenyl)-3-oxopropionate (19.0 g, 63%) asan oil.

IR ν max^(Neat)cm⁻¹: 1732, 1688, 1599, 1510, 1159, 851. ¹H-NMR (CDCl₃)δ:1.12 (3H, t, J=7.1 Hz), 3.29 (2H, d, J=7.4 Hz), 4.01 (2H, q, J=7.1 Hz),4.53 (1H, t, J=7.4 Hz), 6.88-7.30 (6H, m), 7.90-8.08 (2H, m).

2) To a solution of anhydrous zinc chloride (15.4 g, 0.113 mol) indiethyl ether (200 ml) was added sodium borohydride (9.5 g, 0.226 mol)and the mixture was stirred at room temperature for 2 hrs. The insolublematerial was removed by filtration. To the filtrate was added a solutionof ethyl 2-(4-fluorobenzyl)-3-(4-fluorophenyl) 3-oxopropionate (18 g,56.5 mmol) in diethyl ether (50 ml) and the mixture was stirred at roomtemperature for 1 hr. 1N Hydrochloric acid was added to the reactionsolution under ice-cooling to terminate the reaction. Water (200 ml) andethyl acetate (200 ml) were added to the reaction solution and themixture was extracted. The extract was washed with water and saturatedaqueous sodium hydrogen carbonate solution, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethylacetate=10:1-3:1) to give ethyl(2RS,3RS)-2-(4-fluorobenzyl)-3-(4-fluorophenyl)-3-hydroxypropionate(16.8 g, 93%) as a colorless oil.

IR ν max^(Neat)cm⁻¹: 1726, 1713, 1605, 1510, 1225, 1159, 1030, 835.¹H-NMR (CDCl₃)δ: 0.94 (3H, t, J=7.0 Hz), 2.80-3.02 (4H, m), 3.88 (2H, q,J=7.0 Hz), 4.99 (1H, d, J=4.8 Hz), 6.85-7.15 (6H, m), 7.30-7.50 (2H, m).

3) To a solution of ethyl(2RS,3RS)-2-(4-fluorobenzyl)-3-(4-fluorophenyl)-3-hydroxypropionate(16.5 g, 51.5 mmol) in methanol (50 ml) was added 2N aqueous sodiumhydroxide solution (51.5 ml, 0.103 mol) and the mixture was stirred atroom temperature for 3 hrs. The reaction solution was acidified with 1Nhydrochloric acid (130 ml) and extracted with ethyl acetate (200, 100ml). The extract was washed with water, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue wascrystallized from, hexane to give(2RS,3RS)-3-(4-fluorophenyl)-2-(4-fluorobenzyl)-3-hydroxypropionic acid(14.2 g, 94%).

mp 169-170° C. IR ν max^(KBr)cm⁻¹: 1692, 1607, 1510, 1231, 1015, 839,826. elemental analysis for C₁₆H₁₄F₂O₃, Calcd: C, 66.75; H, 4.83. Found:C, 66.76; H, 4.64. ¹H-NMR (DMSO-d₆)δ: 2.70-2.95 (2H, m), 3.05 (1H, d,J=11.0 Hz), 4.60-4.80 (1H, m), 5.65-5.80 (1H, m), 6.97-7.22 (6H, m),7.30-7.45 (2H, m), 11.80-12.00 (1H, br, OH).

4) To a solution of(2RS,3RS)-3-(4-fluorophenyl)-2-(4-fluorobenzyl)-3-hydroxypropionic acid(13.8 g, 47.2 mmol) in tetrahydrofuran (150 ml) were addeddiphenylphosphoryl azide (13.2 ml, 61.4 mmol) and triethylamine (9.2 ml,66.1 mmol) and the mixture was stirred for 30 min. The mixture wasfurther heated under reflux for 4 hrs. and allowed to stand at roomtemperature. Water (200 ml) was added and the mixture was extracted withethyl acetate (200 ml). The extract was washed with 1N hydrochloric acidand saturated aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate, passed through a small amount of silica geland evaporated under reduced pressure. The residue was crystallized fromhexane-ethyl acetate to give(4RS,5SR)-5-(4-fluorophenyl)-4-((4-fluorophenyl)methyl)-1,3-oxazolidin-2-one(12.8 g, 94%) as crystals.

mp 197-198° C. IR ν max^(KBr)cm⁻¹: 1738, 1611, 1510, 1231, 1069, 1013,980, 853. elemental analysis for C₁₆H₁₃F₂NO₂, Calcd: C, 66.43; H, 4.53;N, 4.84. Found: C, 66.39; H, 4.40; N, 4.79. ¹H-NMR (CDCl₃)δ: 2.10-2.35(2H, m), 4.10-4.30 (1H, m), 4.91 (1H, s), 5.79 (1H, d, J=7.6 Hz), 6.98(4H, d, J=7.4 Hz), 7.13 (2H, t, J=8.4 Hz), 7.30-7.43 (2H, m).

5) To a solution of(4RS,5SR)-5-(4-fluorophenyl)-4-((4-fluorophenyl)methyl)-1,3-oxazolidin-2-one(11.87 g, 41.0 mmol) in ethanol (200 ml) was added 8N aqueous sodiumhydroxide solution (25.6 ml, 205 mmol) and the mixture was heated underreflux for 4 hrs. The reaction solution was concentrated, diluted withwater (200 ml) and extracted with ethyl acetate (200 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. The residue was recrystallizedfrom ethyl acetate-hexane to give(1RS,2SR)-2-amino-1,3-bis(4-fluorophenyl)-1-propanol (9.33 g, 86%).

mp 66-67° C. IR ν max^(KBr)cm⁻¹: 1603, 1510, 1225. Anal. Calcd forC₁₅H₁₅F₂NO: C, 68.43; H, 5.74; N, 5.32. Found: C, 68.30; H, 5.68; N,5.17. ¹H-NMR (CDCl₃)δ: 2.32 (1H, dd, J=13.4, 10.2 Hz), 2.77 (1H, dd,J=13.4, 3.0 Hz), 3.16-3.30 (1H, m), 4.64 (1H, d, J=5.2 Hz), 6.90-7.18(6H, m), 7.30-7.42 (2H, m).

6) To a solution of (1RS,2SR)-2-amino-1,3-bis(4-fluorophenyl)-1-propanol(450 mg, 1.71 mmol) in ethyl acetate (15 ml) were added 1-naphthoylchloride (386 ml, 2.56 mmol) and saturated aqueous sodium hydrogencarbonate (15 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (100 ml) andextracted with ethyl acetate (100 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:acetone=1:1). Recrystallization from ethylacetate-hexane gave the title compound (515 mg, 72%).

mp 199-200° C. IR ν max^(KBr)cm⁻¹: 1640, 1605, 1539, 1510. Anal. Calcdfor C₂₆H₂₁F₂NO₂: C, 74.81; H, 5.07; N, 3.36. Found: C, 74.56; H, 5.04;N, 3.27. ¹H-NMR (CDCl₃)δ: 2.75 (1H, dd, J=14.2, 10.6 Hz), 3.01 (1H, dd,J=14.2, 4.0 Hz), 3.63 (1H, d, J=4.0 Hz), 4.68-4.84 (1H, m), 5.04-5.10(1H, m), 5.89 (1H, d, J=8.4 Hz), 6.92-7.30 (7H, m), 7.32-7.52 (5H, m),7.69 (1H, d, J=8.2 Hz), 7.78-7.92 (2H, m).

Example 1454-fluoro-N-((1RS,2SR)-2-(4-fluorophenyl)-1-((4-fluorophenyl)methyl)-2-hydroxyethyl)-7-1-naphthalenecarboxamide

To a solution of (1RS,2SR)-2-amino-1,3-bis(4-fluorophenyl)-1-propanol(450 mg, 1.71 mmol) in acetonitrile (30 ml) were added4-fluoronaphthalenecarboxylic acid (325 mg, 1.71 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (491 mg,2.56 mmol) and 1-hydroxy-1H-benzotriazole (261 mg, 1.71 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica, gel column chromatography (ethyl acetate).Recrystallization from ethyl acetate-hexane gave the title compound (571mg, 77%).

mp 233-234° C. IR ν max^(KBr)cm⁻¹: 1644, 1626, 1601, 1508. Anal. Calcdfor C₂₆H₂₀F₃NO₂: C, 71.72; H, 4.63; N, 3.22. Found: C, 71.58; H, 4.56;N, 3.12. ¹H-NMR (CDCl₃)δ: 2.77 (1H, dd, J=14.4, 11.0 Hz), 3.03 (1H, dd,J=14.4, 4.4 Hz), 3.42-3.50 (1H, m), 4.64-4.84 (1H, m), 5.04-5.12 (1H,m), 5.84 (1H, d, J=8.4 Hz), 6.92-7.32 (8H, m), 7.40-7.60 (4H, m), 7.74(1H, d, J=8.0 Hz), 8.09 (1H, d, J=8.4 Hz).

Example 146N-((1RS,2SR)-2-(4-fluorophenyl)-1-((4-fluorophenyl)methyl)-2-hydroxyethyl)cyclohexanecarboxamide

To a solution of (1RS,2RS)-2-amino-1,3-bis(4-fluorophenyl)-1-propanol(450 mg, 1.71 mmol) in ethyl acetate (15 ml) were addedcyclohexanecarbonyl chloride (342 ml, 2.56 mmol) and saturated aqueoussodium hydrogen carbonate (15 ml) and the mixture was stirred at roomtemperature for 3 hrs. The reaction solution was diluted with water (100ml) and extracted with ethyl acetate (100 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the title compound (553 mg, 87%).

mp 203-204° C. IR ν max^(KBr)cm¹: 1645, 1537, 1512. Anal. Calcd forC₂₂H₂₅F₂NO₂: C, 70.76; H, 6.75; N, 3.75. Found: C, 70.79; H, 6.80; N,3.63. ¹H-NMR (CDCl₃)δ: 1.02-1.38 (5H, m), 1.50-1.80 (5H, m), 1.82-2.04(1H, m), 2.63 (1H, dd, J=14.4, 10.4 Hz), 2.84 (1H, dd, J=14.4, 4.4 Hz),4.06 (1H, d, J=4.0 Hz), 4.30-4.46 (1H, m), 4.90-4.96 (1H, m), 5.29 (1H,d, J=8.4 Hz), 6.90-7.14 (6H, m), 7.30-7.42 (2H, m).

Example 147N-((1RS,2SR)-2-(4-fluorophenyl)-1-((4-fluorophenyl)methyl)-2-hydroxyethyl)-4-phenylbutyramide

To a solution of (1RS,2SR)-2-amino-1,3-bis(4-fluorophenyl)-1-propanol(450 mg, 1.71 mmol) in acetonitrile (30 ml) were added4-phenyl-n-butyric acid (280 mg, 1.71 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (491 mg,2.56 mmol) and 1-hydroxy-1H-benzotriazole (261 mg, 1.71 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate).Recrystallization from ethyl acetate-hexane gave the title compound (523mg, 75%).

mp 147-148° C. IR ν max^(KBr)cm⁻¹: 1645, 1609, 1549. Anal. Calcd forC₂₅H₂₅F₂NO₂: C, 73.33; H, 6.15; N, 3.42. Found: C, 73.34; H, 6.09; N,3.35. ¹H-NMR (CDCl₃)δ: 1.70-1.90 (2H, m), 2.00-2.12 (2H, m), 2.44-2.58(2H, m), 2.62 (1H, dd, J=14.4, 10.4 Hz), 2.80 (1H, dd, J=14.4, 4.4 Hz),3.74 (1H, s), 4.32-4.48 (1H, m), 4.90-4.98 (1H, m), 5.32 (1H, d, J=7.6Hz), 6.84-7.16 (8H, m), 7.20-7.42 (5H, m).

Example 148N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(methyloxy)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

1) A mixture of ethyl 3-(4-fluorophenyl)-3-oxopropionate (20 g, 95.1mmol), 4-methoxybenzyl chloride (11.6 ml, 85.6 mmol), potassiumcarbonate (26.3 g, 0.19 mol) and acetonitrile (300 ml) was stirred at60° C. for 6 hrs. The reaction solution was concentrated under reducedpressure, water (300 ml) was added, and the mixture was extracted withethyl acetate (300 ml×2). The extract was washed with water, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=10:1-5:1) to give ethyl3-(4-fluorophenyl)-3-oxo-2-(4-methoxybenzyl)propionate (26.6 g, 85%) asan oil.

IR ν max^(Neat)cm⁻¹: 1734, 1686, 1597, 1514, 1250, 1179, 1159, 1034,849, 824. ¹H-NMR (CDCl₃)δ: 1.13 (3H, t, J=7.2 Hz), 3.26 (2H, d, J=7.6Hz), 3.76 (3H, s), 4.10 (2H, q, J=7.2 Hz), 4.53 (2H, t, J=7.2 Hz), 6.79(2H, d, J=8.2 Hz), 6.95-7.20 (3H, m), 7.90-8.10 (2H, m).

2) To a solution of zinc chloride (21.2 g, 0.156 mol) in diethyl ether(200 ml) was added sodium borohydride (13.1 g, 0.31 mol) and the mixturewas stirred at room temperature for 2 hrs. The insoluble material wasremoved by filtration. To the filtrate was added a solution of ethyl3-(4-fluorophenyl)-3-oxo-2-(4-methoxybenzyl)propionate (25.7 g, 77.8mmol) in diethyl ether (50 ml) and the mixture was stirred at roomtemperature for 1 hr. 1N Hydrochloric acid was added to the reactionsolution under ice-cooling to terminate the reaction. Water (200 ml) andethyl acetate (200 ml) were added to the mixture and the mixture wasextracted. The extract was washed with water and saturated aqueoussodium hydrogen carbonate solution, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=10:1-3:1) togive ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)propionate(23.3 g, 90%) as a colorless oil.

IR ν max^(Neat)cm⁻¹: 1726, 1607, 1512, 1248, 1223, 1179, 1034, 839.¹H-NMR (CDCl₃)δ: 0.95 (3H, t, J=7.2 Hz), 2.85-3.00 (3H, m), 3.76 (3H, s,OMe), 3.89 (2H, q, J=7.2 Hz), 4.95-5.07 (1H, m), 6.70-6.88 (2H, m),6.93-7.12 (4H, m), 7.30-7.47 (2H, m).

3) To a solution of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)propionate(22.8 g, 68.6 mmol) in methanol (100 ml) was added 2N aqueous sodiumhydride solution (69 ml, 0.137 mol) and the mixture was stirred at roomtemperature for 4 hrs. The reaction solution was acidified with 6Nhydrochloric acid, water (300 ml) was added, and the mixture wasextracted with ethyl acetate (200 ml×2). The extract was washed withwater, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was crystallized from a mixture of hexaneand diethyl ether to give(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)propionic acid(14.8 g, 71%).

mp 96-98° C. IR ν max^(KBr)cm⁻¹: 1690, 1611, 1514, 1254, 1235, 1036,837. elemental analysis for C₁₇H₁₇FO₄, Calcd: C, 67.10; H, 5.63. Found:C, 67.11; H, 5.65. ¹H-NMR (DMSO-d₆)δ: 2.70-2.90 (2H, m), 2.95-3.10 (1H,m), 3.70 (3H, s), 4.60-4.75 (1H, m), 5.60-5.75 (1H, m), 6.79 (2H, d,J=8.8 Hz), 7.00-7.20 (4H, m), 7.30-7.45 (2H, m), 11.80-11.95 (1H, br,OH).

4) To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)propionic acid(13.7 g, 45.0 mmol) in tetrahydrofuran (150 ml) were addeddiphenylphosphoryl azide (12.6 ml, 58.5 mmol) and triethylamine (8.78ml, 63.0 mmol) and the mixture was stirred for 30 min. The mixture wasfurther heated under reflux for 4 hrs and allowed to stand at roomtemperature. Water (2.00 ml) was added and the mixture was extractedwith ethyl acetate (200 ml). The extract was washed with 1N hydrochloricacid and saturated aqueous sodium hydrogen carbonate solution, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was purified by silica gel column chromatography(chloroform:ethyl acetate=4:1-2:1) to give(4RS,5SR)-5-(4-fluorophenyl)-4-((4-(methyloxy)phenyl)methyl)-1,3-oxazolidin-2-one(13.0 g, 96%) as crystals.

mp 125-126° C. IR ν max^(KBr)cm⁻¹: 1738, 1613, 1514, 1248, 1107, 1036,845, 824. elemental analysis for C₁₇H₁₆FNO₃.1/4H₂O, Calcd: C, 66.77; H,5.44; N, 4.58. Found: C, 66.57; H, 5.31; N, 4.49. ¹H-NMR (CDCl₃)δ:2.10-2.30 (3H, m), 3.78 (3H, s), 4.10-4.30 (1H, m), 4.94 (1H, brs), 5.78(1H, d, J=7.6 Hz), 6.78-6.90 (2H, m), 6.90-7.00 (2H, m), 7.07-7.20 (2H,m), 7.30-7.45 (2H, m).

5) To a solution of(4RS,5SR)-5-(4-fluorophenyl)-4-((4-(methyloxy)phenyl)methyl)-1,3-oxazolidin-2-one(12.8 g, 42.5 mmol) in ethanol (200 ml) was added 8N aqueous sodiumhydroxide solution (26.6 ml, 210 mmol) and the mixture was heated underreflux for 4 hrs. The reaction solution was concentrated, diluted withwater (200 ml) and extracted with ethyl acetate (200 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. The residue was recrystallizedfrom ethyl acetate-hexane to give(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(methyloxy)phenyl)-1-propanol(10.08 g, 86%).

mp 78-79° C. IR ν max^(KBr)cm⁻¹: 1611, 1603, 1584, 1512. Anal. Calcd forC₁₆H₁₈FNO₂: C, 69.80; H, 6.59; N, 5.09. Found: C, 69.69; H, 6.65; N,5.00. ¹H-NMR (CDCl₃)δ: 2.27 (1H, dd, J=13.8, 10.4 Hz), 2.72 (1H, dd,J=13.8, 3.2 Hz), 3.16-3.28 (1H, m), 3.78 (3H, s), 4.65 (1H, d, J=4.6Hz), 6.78-6.86 (2H, m), 7.00-7.12 (4H, m), 7.32-7.72 (2H, m).

6) To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(methyloxy)phenyl)-1-propanol(450 mg, 1.64 mmol) in ethyl acetate (15 ml) were added 1-naphthoylchloride (369 ml, 2.45 mmol) and saturated aqueous sodium hydrogencarbonate (15 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (100 ml) andextracted with ethyl acetate (100 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was recrystallized from ethylacetate-hexane to give the title compound (622 mg, 89%).

mp 198-199° C. IR ν max^(KBr)cm⁻¹: 1640, 1611, 1541, 1510. Anal. Calcdfor C₂₇H₂₄FNO₃: C, 75.51; H, 5.63; N, 3.26. Found: C, 75.25; H, 5.88; N,3.18. ¹H-NMR (CDCl₃)δ: 2.69 (1H, dd, J=14.2, 10.6 Hz), 3.01 (1H, dd,J=14.2, 4.0 Hz), 3.80 (3H, s), 3.93 (1H, d, J=4.0 Hz), 4.70-4.88 (1H,m), 5.02-5.10 (1H, m), 5.82 (1H, d, J=8.2 Hz), 6.86 (2H, d, J=8.6 Hz),7.00-7.20 (4H, m), 7.20-7.52 (6H, m), 7.73 (1H, d, J=8.0 Hz), 7.80-7.92(2H, m).

Example 1494-fluoro-N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(methyloxy)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(methyloxy)phenyl)-1-propanol(450 mg, 1.64 mmol) in acetonitrile (30 ml) were added4-fluoronaphthalenecarboxylic acid (311 mg, 1.64 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (470 mg,2.43 mmol) and 1-hydroxy-1H-benzotriazole (250 mg, 1.64 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted-with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=1:1).Recrystallization from ethyl acetate-hexane gave the title compound (558mg, 76%).

mp 210-211° C. IR ν max^(KBr)cm⁻¹: 1640, 1624, 1599, 1539, 1512. Anal.Calcd for C₂₇H₂₃F₂NO₃: C, 72.47; H, 5.18; N, 3.13. Found: C, 72.39; H,5.08; N, 3.01. ¹H-NMR (CDCl₃)δ: 2.70 (1H, dd, J=14.4, 10.8 Hz), 3.00(1H, dd, J=14.4, 4.0 Hz), 3.80 (3H, s), 3.84 (1H, d, J=3.6 Hz),4.66-4.84 (1H, m), 5.02-5.10 (1H, m), 5.81 (1H, d, J=7.6 Hz), 6.85 (2H,d, J=8.8 Hz), 6.92-7.22 (6H, m), 7.40-7.60 (4H, m), 7.76 (1H, d, J=8.4Hz), 8.08 (1H, d, J=8.0 Hz).

Example 150N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(methyloxy)phenyl)methyl)ethyl)cyclohexanecarboxamide

A solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(methyloxy)phenyl)-1-propanol(450 mg, 1.64 mmol) in ethyl acetate (15 ml) were addedcyclohexanecarbonyl chloride (328 ml, 2.45 mmol) and saturated aqueoussodium hydrogen carbonate (15 ml) and the mixture was stirred overnightat room temperature. The reaction solution was diluted with water (100ml) and extracted with ethyl acetate (100 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the title compound (529 mg, 84%).

mp 193-194° C. IR ν max^(KBr)cm⁻¹: 1647, 1539, 1512. Anal. Calcd forC₂₃H₂₈FNO₃: C, 71.66; H, 7.32; N, 3.63. Found: C, 71.57; H, 7.40; N,3.55. ¹H-NMR (CDCl₃)δ: 1.02-1.40 (5H, m), 1.54-1.80 (5H, m), 1.88-2.08(1H, m), 2.56 (1H, dd, J=14.4, 10.2 Hz), 2.82 (1H, dd, J=14.4, 5.2 Hz),3.78 (3H, s), 4.30-4.50 (1H, m), 4.45 (1H, d, J=4.4 Hz), 4.88-4.92 (1H,m), 5.24 (1H, d, J=7.0 Hz), 6.81 (2H, d, J=8.8 Hz), 6.98-7.10 (4H, m),7.28-7.40 (2H, m).

Example 151N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(methyloxy)phenyl)methyl)ethyl)-4-phenylbutyramide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(methyloxy)phenyl)-1-propanol(450 mg, 1.64 mmol) in acetonitrile (30 ml) were added4-phenyl-n-butyric acid (268 mg, 1.64 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (470 mg,2.45 mmol) and 1-hydroxy-1H-benzotriazole (250 mg, 1.64 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:acetone=1:1).Recrystallization from ethyl acetate-hexane gave the title compound (575mg, 83%).

mp 130-131° C. Ir ν max^(KBr)cm⁻¹: 1645, 1607, 1512. Anal. Calcd forC₂₆H₂₈FNO₃: C, 74.09; H, 6.70; N, 3.32. Found: C, 74.05; H, 6.82; N,3.24. ¹H-NMR (CDCl₃)δ: 1.70-1.90 (2H, m), 2.00-2.12 (2H, m), 2.40-2.62(3H, m), 2.80 (1H, dd, J=14.2, 4.4 Hz), 3.72 (3H, s), 4.05 (1H, d, J=4.4Hz), 4.32-4.48 (1H, m), 4.88-4.98 (1H, m), 5.27 (1H, d, J=7.2 Hz), 6.79(2H, d, J=8.6 Hz), 6.96-7.14 (6H, m), 7.16-7.40 (5H, m).

Example 152 tert-butylN-[(1RS,2SR)-1-(4-cyanobenzyl)-2-(4-fluorophenyl)-2-hydroxyethyl]carbamate

1) ethyl 2-(4-cyanobenzyl)-3-(4-fluorophenyl)-3-oxopropionate

To a solution of ethyl (4-fluorobenzoyl)acetate (15.30 g, 72.79 mmol) in1,2-dimethoxyethane (100 ml) was added a suspension (2.91 g, 72.8 mmol)of 60% sodium hydride in liquid paraffin under ice-cooling and themixture was stirred as it was for 0.5 hr. A solution of 4-cyanobenzylbromide (14.3 g, 72.8 mmol) in 1,2-dimethoxyethane (50 ml) was added atroom temperature and the mixture was stirred at room temperature for 4hrs. The reaction solution was poured into water and extracted twicewith ethyl acetate. The collected organic layer was dried over anhydrousmagnesium sulfate and the solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography(hexane/toluene=1/1-1/1.5) and crystallized from diethyl ether-hexane togive the objective substance.

white crystal yield 20.60 g, 87% mp 85-86° C.; ¹H-NMR (CDCl₃, 200 MHz) δ1.12 (3H, t, J=7.2 Hz), 3.38 (2H, d, J=7.2 Hz), 4.10 (2H, q, J=7.1 Hz),4.56 (1H, t, J=7.5 Hz), 7.14 (2H, t, J=8.6 Hz), 7.35 (2H, d, J=8.0 Hz),7.56 (2H, d, J=8.0 Hz), 8.00 (2H, dd, J=5.4 Hz, 9.0 Hz); IR (KBr) 2230,1730, 1692, 1599, 1508, 1306, 1285, 1236, 1202, 1161, 851 cm⁻¹; Anal.Calcd for C₁₉H₁₆FNO₃: C, 70.14; H, 4.96; N, 4.31. Found: C, 70.20; H,4.84; N, 4.29.

2) ethyl(2RS,3RS)-2-(4-cyanobenzyl)-3-(4-fluorophenyl)-3-hydroxypropionate

While stirring zinc chloride (8.52 g, 62.5 mmol) in diethyl ether (100ml), sodium borohydride (4.73 g, 125 mmol) was added at room temperatureand the mixture was stirred as it was for 2 hrs. The insoluble materialof the mixture was removed by filtration and washed with diethyl etherto give a solution of zinc borohydride in diethyl ether. To the obtainedsolution was added a solution of ethyl2-(4-cyanobenzyl)-3-(4-fluorophenyl)-3-oxopropionate (10.17 g, 31.26mmol) in diethyl ether (50 ml) at room temperature and the mixture wasstirred as it was for 2 hrs. Dilute hydrochloric acid was added to thereaction solution by small portions to decompose excess zincborohydride. The mixture was extracted twice with ethyl acetate. Thecollected organic layer was dried over anhydrous magnesium sulfate andthe solvent was evaporated under reduced pressure. The obtained crudeproduct was purified by silica gel column chromatography (hexane/ethylacetate=3/1-2/1) to give the objective substance.

colorless liquid yield 4.297 g, 42% ¹H-NMR (CDCl₃, 200 MHz) δ 0.93 (3H,t, J=7.1 Hz), 2.82 (1H, d, J=2.8 Hz), 2.89-3.08 (3H, m), 3.88 (2H, q,J=7.2 Hz), 5.03 (1H, dd, J=2.5 Hz, 5.1 Hz), 7.05 (2H, t, J=8.8 Hz), 7.20(2H, d, J=8.4 Hz), 7.37 (2H, dd, J=5.2 Hz, 8.4 Hz), 7.53 (2H, d, J=8.4Hz); IR (neat) 3484, 2230, 1725, 1607, 1508, 1223, 1179, 1159, 1032, 839cm⁻¹

3) (2RS,3RS)-2-(4-cyanobenzyl)-3-(4-fluorophenyl)-3-hydroxypropionicacid

To a solution of ethyl(2RS,3RS)-2-(4-cyanobenzyl)-3-(4-fluorophenyl)-3-hydroxypropionate(4.145 g, 12.66 mmol) in methanol (30 ml)—tetrahydrofuran (20 ml) wasadded 1N aqueous sodium hydroxide solution (25.3 ml, 25.3 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas concentrated, diluted with water, acidified with 1N hydrochloricacid and extracted twice with ethyl acetate. The collected organic layerwas dried over anhydrous sodium sulfate and the solvent was evaporatedunder reduced pressure. The residue was crystallized from diethylether-hexane to give the objective substance.

white crystal yield 3.559 g, 94% mp 165-168° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.89-3.15 (3H, m), 5.03 (1H, d, J=5.0 Hz), 7.03 (2H, t, J=8.6Hz), 7.24 (2H, d, J=8.2 Hz), 7.40 (2H, dd, J=5.5 Hz, 8.5 Hz), 7.51 (2H,d, J=8.4 Hz); IR (KBr) 3476, 3152, 2232, 1719, 1678, 1605, 1508, 1406,1225, 1175, 1157, 845 cm⁻¹; Anal. Calcd for C₁₇H₁₄FNO₃: C, 68.22; H,4.71; N, 4.68. Found: C, 67.98; H, 4.83; N, 4.47.

4) (4RS,5SR)-4-(4-cyanobenzyl)-5-(4-fluorophenyl)-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-2-(4-cyanobenzyl)-3-(4-fluorophenyl)-3-hydroxypropionic acid(3.385 g, 11.31 mmol) in tetrahydrofuran (50 ml) were addedtriethylamine (2.36 ml, 17.0 mmol) and diphenylphosphoryl azide (3.42 g,12.4 mmol) and the mixture, was heated under reflux overnight. Thesolvent of the reaction solution was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/2) and crystallized fromdiethyl ether-hexane to give the objective substance.

white crystal yield 2.741 g, 82% mp 170-173° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.36 (2H, d, J=6.6 Hz), 4.27 (1H, dt, J=7.5 Hz, 7.5 Hz), 5.17 (1H, brs), 5.81 (1H, d, J=7.8 Hz), 7.13 (2H, t, J=8.6 Hz), 7.13 (2H, d, J=8.0Hz), 7.35 (2H, dd, J=5.2 Hz, 8.4 Hz), 7.59 (2H, d, J=8.0 Hz); IR (KBr)3324, 2240, 1748, 1514, 1225 cm⁻¹; Anal. Calcd for C₁₇H₁₃FN₂O₂: C,68.91; H, 4.42; N, 9.45. Found: C, 68.98; H, 4.43; N, 9.33.

5) tert-butyl(4RS,5SR)-4-(4-cyanobenzyl)-5-(4-fluorophenyl)-2-oxo-1,3-oxazolidine-3-carboxylate

A solution of(4RS,5SR)-4-(4-cyanobenzyl)-5-(4-fluorophenyl)-1,3-oxazolidin-2-one(2.622 g, 8.849 mmol), di-tert-butyl dicarbonate (2.32 g, 10.6 mmol) and4-N,N-dimethylaminopyridine (0.11 g, 0.88 mmol) in acetonitrile (30 ml)was stirred overnight at room temperature. The reaction solution wasdiluted with ethyl acetate, washed with water, dried over anhydrousmagnesium sulfate and passed through silica gel. The solvent wasevaporated under reduced pressure. The obtained residue was crystallizedfrom ethyl acetate-hexane to give the objective substance.

white crystal yield 3.243 g, 92% mp 161-163° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.51 (9H, s), 2.63 (1H, dd, J=8.6 Hz, 14.2 Hz), 2.93 (1H, dd, J=4.7Hz, 14.3 Hz), 4.74-4.85 (1H, m), 5.68 (1H, d, J=6.6 Hz), 6.80 (2H, d,J=8.0 Hz), 7.00 (2H, t, J=8.6 Hz), 7.16 (2H, dd, J=5.4 Hz, 8.6 Hz), 7.39(2H, d, J=8.0 Hz); IR (KBr) 2982, 2228, 1815, 1721, 1514, 1368, 1152,1069 cm⁻¹; Anal. Calcd for C₂₂H₂₁FN₂O₄: C, 66.66; H, 5.34; N, 7.07.Found: C, 66.76; H, 5.37; N, 7.09.

6) tert-butylN-[(1RS,2SR)-1-(4-cyanobenzyl)-2-(4-fluorophenyl)-2-hydroxyethyl]carbamate

To a solution of tert-butyl(4RS,5SR)-4-(4-cyanobenzyl)-5-(4-fluorophenyl)-2-oxo-1,3-oxazolidine-3-carboxylate(3.014 g, 7.603 mmol) in methanol (20 ml) and tetrahydrofuran (10 ml)was added a solution of sodium hydroxide (0.33 g, 8.36 mmol) in methanol(20 ml) under ice-cooling and the mixture was stirred at roomtemperature for 3 hrs. The reaction solution was diluted with ethylacetate, washed with dilute hydrochloric acid, dried over anhydrousmagnesium sulfate and passed through silica gel. The solvent wasevaporated under reduced pressure. The obtained residue was crystallizedfrom ethyl acetate-hexane to give the objective substance.

white crystal yield 2.366 g, 84% mp 203-204° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.33 (9H, s), 2.67-2.98 (3H, m), 4.06 (1H, br s), 4.63 (1H, br d,J=8.4 Hz), 4.93 (1H, br s), 7.07 (2H, t, J=8.6 Hz), 7.21 (2H, d, J=8.2Hz), 7.38 (2H, dd, J=5.4 Hz, 8.6 Hz), 7.54 (2H, d, J=8.4 Hz); IR (KBr)3466, 3366, 2236, 1684, 1508, 1530, 1221, 1171 cm⁻¹; Anal. Calcd forC₂₁H₂₃FN₂O₃: C, 68.09; H, 6.26; N, 7.56. Found: C, 68.20; H, 6.18; N,7.60.

Example 153N-[(1RS,2SR)-1-(4-cyanobenzyl)-2-(4-fluorophenyl)-2-hydroxyethyl]-4-fluoronaphthalene-1-carboxamide

1) (1RS,2SR)-2-amino-3-(4-cyanophenyl)-1-(4-fluorophenyl)propan-1-ol

A solution of tert-butylN-[(1RS,2SR)-1-(4-cyanobenzyl)-2-(4-fluorophenyl)-2-hydroxyethyl]carbamate(2.199 g, 5.937 mmol) and conc. hydrochloric acid (4 ml) in methanol (30ml)—tetrahydrofuran (20 ml) was stirred at 60° C. for 30 min. Thereaction solution was diluted with water, alkalified with potassiumcarbonate and extracted twice with ethyl acetate. The collected organiclayer was dried over anhydrous sodium sulfate and the solvent wasevaporated under reduced pressure. The residue was allowed toprecipitate with diethyl ether-hexane to give the objective substance.

white amorphous powder yield 1.557 g, 97% ¹H-NMR (CDCl₃, 200 MHz) δ 2.44(1H, dd, J=10.3 Hz, 13.5 Hz), 2.88 (1H, dd, J=2.9 Hz, 13.9 Hz), 3.28(1H, ddd, J=3.2 Hz, 5.1 Hz, 10.2 Hz), 4.64 (1H, d, J=5.2 Hz), 7.08 (2H,t, J=8.8 Hz), 7.27 (2H, d, J=8.6 Hz), 7.37 (2H, dd, J=5.6 Hz, 8.8 Hz),7.58 (2H, d, J=8.0 Hz); IR (KBr) 3350-2750, 2224, 1605, 1507, 1221,1044, 828 cm⁻¹; Anal. Calcd for C₁₆H₁₅FN₂O. 0.2H₂O: C, 70.16; H, 5.67;N, 10.23. Found: C, 70.55; H, 5.84; N, 9.95.

2)N-[(1RS,2SR)-1-(4-cyanobenzyl)-2-(4-fluorophenyl)-2-hydroxyethyl]-4-fluoronaphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-3-(4-cyanophenyl)-1-(4-fluorophenyl)propan-1-ol (0.168g, 0.622 mmol), 4-fluoro-1-naphthoate (0.12 g, 0.62 mmol) and1-hydroxybenzotriazole hydrate (0.10 g, 0.62 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.12g, 0.62 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white crystal yield 0.217 g, 79% mp 248-249° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.93 (1H, dd, J=11.0 Hz, 14.4 Hz), 3.14 (1H, dd, J=3.4 Hz,13.6 Hz), 4.64-4.79 (1H, m), 4.94 (1H, t, J=4.6 Hz), 5.42 (1H, d, J=4.2Hz), 7.02-7.12 (3H, m), 7.20 (1H, dd, J=5.5 Hz, 7.7 Hz), 7.37-7.58 (9H,m), 7.78 (1H, d, J=9.4 H), 8.05 (1H, d, J=7.6 Hz); IR (KBr) 3476, 3291,2232, 1642, 1626, 1603, 1537, 1508, 1225, 847 cm⁻¹; Anal. Calcd forC₂₇H₂₀F₂N₂O₂: C, 73.29; H, 4.56; N, 6.33. Found: C, 73.08; H, 4.43; N,6.10.

Example 1544-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-(4-isopropylbenzyl)ethyl]naphthalene-1-carboxamide

1) ethyl 3-(4-fluorophenyl)-2-(4-isopropylbenzyl)-3-oxopropionate

To a solution of ethyl (4-fluorobenzoyl)acetate (23.21 g, 110.4 mmol) in1,2-dimethoxyethane (150 ml) was added a suspension (4.42 g, 110 mmol)of 60% sodium hydride in liquid paraffin under ice-cooling and themixture was stirred as it was for 0.5 hr. A solution of4-isopropylbenzyl chloride (18.6 g 110 mmol) in 1,2-dimethoxyethane (50ml) was added at room temperature and the mixture was stirred at 70° C.overnight. The reaction solution was poured into water and extractedtwice with ethyl acetate. The collected organic layer was dried overanhydrous magnesium sulfate and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate=15/1-9/1) to give the objectivesubstance.

yellow liquid yield 21.01 g, 56% ¹H-NMR (CDCl₃, 200 MHz) δ 1.12 (3H, t,J=7.1 Hz), 1.20 (6H, d, J=7.0 Hz), 2.78-2.91 (1H, m), 3.28 (2H, d, J=7.2Hz), 4.10 (2H, q, J=7.1 Hz), 4.55 (1H, t, J=7.3 Hz), 7.06-7.26 (6H, m),7.98 (2H, dd, J=5.7 Hz, 8.7 Hz); IR (neat) 2961, 1738, 1688, 1599, 1508,1271, 1235, 1159, 849 cm⁻¹

2) ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(4-isopropylbenzyl)propionate

While stirring zinc chloride (8.41 g, 61.7 mmol) in diethyl ether (100ml), sodium borohydride (4.67 g, 123 mmol) was added at room temperatureand the mixture was stirred as it was for 2 hrs. The insoluble materialof the mixture was removed by filtration and washed with diethyl etherto give a solution of zinc borohydride in diethyl ether. To the obtainedsolution was added a solution of ethyl3-(4-fluorophenyl)-2-(4-isopropylbenzyl)-3-oxopropionate (10.57 g, 30.87mmol) in diethyl ether (50 ml) at room temperature and the mixture wasstirred as it was for 2 hrs. Dilute hydrochloric acid was added to thereaction solution by small portions to decompose excess zincborohydride. The mixture was extracted twice with ethyl acetate. Thecollected organic layer was dried over anhydrous magnesium sulfate andthe solvent was evaporated under reduced pressure. The obtained crudeproduct was purified by silica gel column chromatography (hexane/ethylacetate=6/1−3/1) to give the objective substance.

colorless liquid yield 8.433 g, 79% ¹H-NMR (CDCl₃, 200 MHz) δ 0.91 (3H,t, J=7.1 Hz), 1.20 (6H, d, J=7.0 Hz), 2.71-3.09 (4H, m), 3.80-4.96 (2H,m), 5.00 (1H, s), 6.94-7.11 (6H, m), 7.37 (2H, dd, J=5.6 Hz, 8.6 Hz); IR(neat) 3445, 2961, 1726, 1713, 1510, 1225, 1157, 1032, 837 cm⁻¹

3) (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(4-isopropylbenzyl)propionicacid

To a solution of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(4-isopropylbenzyl)propionate(8.267 g, 24.00 mmol) in methanol (40 ml) and tetrahydrofuran (50 ml)was added 1N aqueous sodium hydroxide solution (48.0 ml, 48.0 mmol) andthe mixture was stirred overnight at room temperature. The reactionsolution was concentrated, diluted with water, acidified with 1Nhydrochloric acid and extracted twice with ethyl acetate. The collectedorganic layer was dried over anhydrous sodium sulfate and the solventwas evaporated under reduced pressure. The residue was crystallized fromdiethyl ether-hexane to give the objective substance.

white crystal yield 6.275 g, 83% mp 147-148° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.21 (6H, d, J=7.0 Hz), 2.78-3.09 (4H, m), 5.04 (1H, d, J=4.4 Hz),6.98-7.12 (6H, m), 7.36 (2H, dd, J=5.2 Hz, 8.6 Hz); IR (KBr) 3330,3050-2600, 1690, 1518, 1240, 1221, 1196, 849, 839 cm⁻¹; Anal. Calcd forC₁₉H₂₁FO₃: C, 72.13; H, 6.69. Found: C, 72.03; H, 6.55.

4)(4RS,5SR)-5-(4-fluorophenyl)-4-(4-isopropylbenzyl)-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(4-isopropylbenzyl)propionicacid (6.128 g, 19.37 mmol) in tetrahydrofuran (80 ml) were addedtriethylamine (4.05 ml, 29.1 mmol) and diphenylphosphoryl azide (5.86 g,21.3 mmol) and the mixture was heated under reflux overnight. Thesolvent of the reaction solution was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1) and crystallized fromtoluene-hexane to give the objective substance.

white crystal yield 5.680 g, 94% mp 185-186° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.22 (6H, d, J=7.0 Hz), 2.10-2.30 (2H, m), 2.80-2.94 (1H, m), 4.20(1H, ddd, J=4.2 Hz, 7.8 Hz, 10.4 Hz), 4.90 (1H, br s), 5.79 (1H, d,J=7.6 Hz), 6.95 (2H, d, J=8.0 Hz), 7.09-7.18 (4H, m), 7.37 (2H, dd,J=5.2 Hz, 8.8 Hz); IR (KBr) 3262, 2961, 1738, 1514, 1231, 1009, 855cm⁻¹; Anal. Calcd for C₁₉H₂₀FNO₂: C, 72.82; H, 6.43; N, 4.47. Found: C,72.68; H, 6.30; N, 4.65.

5) (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-isopropylphenyl)propan-1-ol

(4RS,5SR)-5-(4-Fluorophenyl)-4-(4-isopropylbenzyl)-1,3-oxazolidin-2-one(5.503 g, 17.56 mmol) and sodium hydroxide (2.81 g, 70.2 mmol) wereheated under reflux in ethanol (40 ml) and water (3 ml) for 7 hrs. Thereaction solution was diluted with water and stirred at room temperaturefor 10 min. The resulting precipitate was collected by filtration andwashed with water to give the objective substance.

white crystal yield 4.097 g, 81% mp 74-75° C.; ¹H-NMR (CDCl₃, 200 MHz) δ1.23 (6H, d, J=6.8 Hz), 2.29 (1H, dd, J=10.4 Hz, 13.8 Hz), 2.75 (1H, dd,J=2.8 Hz, 13.2 Hz), 2.80-2.94 (1H, m), 3.26 (1H, ddd, J=3.5 Hz, 4.8 Hz,10.5 Hz), 4.66 (1H, d, J=5.2 Hz), 7.03-7.17 (6H, m), 7.37 (2H, dd, J=5.6Hz, 8.4 Hz); IR (KBr) 3627, 3349, 3281, 3150-2700, 1507, 1219, 1042,855, 924 cm⁻¹; Anal. Calcd for C₁₈H₂₂FNO.0.2H₂O: C, 74.30; H, 7.76; N,4.81. Found: C, 74.38; H, 7.80; N, 4.65.

6)4-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-(4-isopropylbenzyl)ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-isopropylphenyl)propan-1-ol(0.164 g, 0.571 mmol), 4-fluoro-1-naphthoate (0.11 g, 0.57 mmol) and1-hydroxybenzotriazole hydrate (87 mg, 0.57 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11g, 0.57 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white crystal yield 0.211 g, 80% mp 189-192° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 1.23 (6H, d, J=6.8 Hz), 2.77-3.06 (3H, m), 4.62-4.76 (1H, m),4.95 (1H, t, J=4.2 Hz), 5.33 (1H, d, J=4.0 Hz), 6.99-7.24 (8H, m),7.37-7.65 (6H, m), 8.04 (1H, d, J=8.6 Hz); IR (KBr) 3299, 2959, 1642,1626, 1539, 1512, 1227, 835 cm⁻¹; Anal. Calcd for C₂₉H₂₇F₂NO₂: C, 75.80;H, 5.92; N, 3.05. Found: C, 75.67; H, 5.77; N, 2.87.

Example 155N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-(4-isopropylbenzyl)ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-isopropylphenyl)propan-1-ol(0.219 g, 0.762 mmol), 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylicacid (0.14 g, 0.76 mmol) and 1-hydroxybenzotriazole hydrate (0.12 g,0.76 mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g,0.76 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white powder yield 0.294 g, 84% mp 168-169° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.23 (6H, d, J=7.0 Hz), 1.95-2.06 (2H, m), 2.14-2.23 (2H, m),2.61-2.76 (3H, m), 2.86 (1H, dd, J=6.6 Hz, 14.0 Hz), 2.97 (1H, dd, J=4.4Hz, 13.6 Hz), 4.14 (1H, d, J=4.4 Hz), 4.61-4.74 (1H, m), 5.02 (1H, t,J=3.1 Hz), 5.63 (1H, d, J=7.8 Hz), 5.93 (1H, td, J=5.7 Hz, 11.3 Hz),6.24 (1H, d, J=11.8 Hz), 6.89 (1H, d, J=7.4 Hz), 7.00-7.18 (8H, m), 7.42(2H, dd, J=5.4 Hz, 8.6 Hz); IR (KBr) 3291, 1638, 1534, 1512, 1225, 1038,826 cm⁻¹; Anal. Calcd for C₃₀H₃₂FNO₂: C, 78.75; H, 7.05; N, 3.06. Found:C, 78.66; H, 6.98; N, 3.06.

Example 156N-((1RS,2SR)-2-(4-fluorophenyl)-1-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-hydroxyethyl)-4-fluoro-1-naphthalenecarboxamide

1) To a solution of 3-fluoro-4-(trifluoromethyl)benzoic acid (10.5 g,50.7 mmol) in tetrahydrofuran (30 ml) was added a 1M tetrahydrofuransolution of borane (63 ml, 63 mmol) and the mixture was stirred at roomtemperature for 8 hrs. 1N Hydrochloric acid (100 ml) was added to thereaction solution and the mixture was extracted with ethyl acetate (300ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate) to give3-fluoro-4-(trifluoromethyl)benzyl alcohol (10.3 g, purity 90%, 94%).

¹H-NMR (CDCl₃)δ: 1.91 (1H, t, J=5.4 Hz), 4.78 (2H, d, J=5.4 Hz),7.16-7.30 (2H, m), 7.59 (1H, t, J=7.6 Hz).

2) To absolution of 3-fluoro-4-(trifluoromethyl)benzyl alcohol (10 g, 52mmol) in chloroform (20 ml) was added thionyl chloride (18.5 ml, 257mmol) and the mixture was heated under ref lux for 4 hrs. The reactionsolution was concentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) to give3-fluoro-4-(trifluoromethyl)benzyl chloride (9.52 g, 87%).

IR ν max^(KBr)cm⁻¹: 1634, 1589, 1512, 1435. ¹H-NMR (CDCl₃)δ: 4.58 (2H,s), 7.20-7.32 (2H, m), 7.60 (1H, t, J=7.6 Hz).

3) To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (8.9 g,42.3 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60%in oil, 1.69 g, 42.3 mmol) under ice-cooling and the mixture was stirredat room temperature for 30 min. To the reaction solution was dropwiseadded a solution of 3-fluoro-4-(trifluoromethyl)benzyl bromide (9.0 g,42.3 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution wasstirred at room temperature for 3 hrs. The reaction solution was pouredinto water (200 ml) and extracted with ethyl acetate (200 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography(toluene:hexane=1:1-toluene) and recrystallized from diisopropylether-hexane to give ethyl3-(4-fluorophenyl)-2-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-oxopropionate(10.8 g, 66%).

mp 56-57° C. IR ν max^(KBr)cm⁻¹: 1738, 1688, 1630, 1599, 1508. Anal.Calcd for C₁₉H₁₅O₃F₅: C, 59.07; H, 3.91. Found: C, 59.10; H, 3.68.¹H-NMR (CDCl₃)δ: 1.13 (3H, t, J=7.2 Hz), 3.37 (2H, d, J=7.2 Hz), 4.12(2H, q, J=7.2 Hz), 4.57 (1H, t, J=7.2 Hz), 7.02-7.20 (4H, m), 7.50 (1H,t, J=8.0 Hz), 7.96-8.10 (2H, m).

4) To a solution of zinc chloride (7.06 g, 51.8 mmol) in diethyl ether(100 ml) was added sodium borohydride (3.92 g, 103.5 mmol) and themixture was stirred at room temperature for 30 min. The insolublematerial was filtered off. To the filtrate was added a solution of ethyl3-(4-fluorophenyl)-2-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-oxopropionate(10 g, 25.9 mmol) in diethyl ether (50 ml) and the mixture was stirredat room temperature for 30 min. 1N Hydrochloric acid was added to thereaction solution under ice-cooling for quenching, water (200 ml) wasadded, and the mixture was extracted with ethyl acetate (300 ml×2). Theextract was ashed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate) to giveethyl(2RS,3RS)-3-(4-fluorophenyl)-2-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-hydroxypropionate(10.0 g, 99%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1715, 1632, 1607, 1584. Anal. Calcd for C₁₉H₁₇O₃F₅:C, 58.77; H, 4.41. Found: C, 58.54; H, 4.51. ¹H-NMR (CDCl₃)δ: 0.95 (3H,t, J=7.2 Hz), 2.86-3.10 (4H, m), 3.91 (2H, q, J=7.2 Hz), 4.98-5.06 (1H,m), 6.90-7.10 (4H, m), 7.30-7.50 (3H, m).

5) To a solution of ethyl(2RS,3RS)-3-(4-fluorophenyl)-2-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-hydroxypropionate(9.9 g, 25.5 mmol) in methanol (40 ml) was added 2N aqueous sodiumhydroxide solution (25.5 ml, 51.0 mmol) and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to give(2RS,3RS)-3-(4-fluorophenyl)-2-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-hydroxypropionicacid (8.3 g, 90%).

mp 74-75° C. IR ν max^(KBr)cm¹: 1713, 1632, 1607, 1586, 1512, 1435.¹H-NMR (CDCl₃)δ: 2.80-3.16 (3H, m), 5.09 (1H, d, J=4.2 Hz), 6.88-7.12(4H, m), 7.30-7.52 (3H, m).

6) To a solution of(2RS,3RS)-3-(4-fluorophenyl)-2-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-3-hydroxypropionicacid (7.0 g, 19.4 mmol) in tetrahydrofuran (180 ml) were addeddiphenylphosphoryl azide (4.6 ml, 21.4 mmol) and triethylamine (4.1 ml,29.2 mmol) and the mixture was heated under reflux for 6 hrs. Thereaction solution was allowed to stand at room temperature, water (200ml) was added, and the mixture was extracted with ethyl acetate (200ml×2). The extract was washed successively with 1N hydrochloric acid,saturated aqueous sodium hydrogen carbonate and saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate). The residue was recrystallized from ethyl acetate-hexane togive(4RS,5SR)-5-(4-fluorophenyl)-4-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(5.26 g, 76%).

mp 122-123° C. IR ν max^(KBr)cm⁻¹: 1759, 1632, 1611, 1586, 1514, 1435.Anal. Calcd for C₁₇H₁₂O₂F₅N: C, 57.15; H, 3.39; N, 3.92. Found: C,57.18; H, 3.39; N, 3.75. ¹H-NMR (CDCl₃)δ: 2.35 (2H, d, J=7.4 Hz),4.22-4.36 (1H, m), 5.44 (1H, s), 5.80 (1H, d, J=7.8 Hz), 6.80-6.96 (2H,m), 7.04-7.20 (2H, m), 7.22-7.42 (2H, m), 7.46-8.00 (1H, m).

7) To a solution of(4RS,5SR)-5-(4-fluorophenyl)-4-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(4.0 g, 11.2 mmol) in ethanol (70 ml) was added 8N aqueous sodiumhydroxide solution (7.0 ml, 56 mmol) and the mixture was heated underreflux for 6 hrs. The reaction solution was concentrated, diluted withwater (300 ml) and extracted with ethyl acetate (300 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. The residue was recrystallizedfrom ethyl acetate-hexane to give(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-fluoro-4-(trifluoromethyl)phenyl)-1-propanol(3.21 g, 87%).

mp 86-87° C. IR ν max^(KBr)cm⁻¹: 1630, 1590, 1508, 1433, 1331. Anal.Calcd for C₁₆H₁₄F₅NO: C, 58.01; H, 4.26; N, 4.23. Found: C, 58.02; H,4.29; N, 4.00. ¹H-NMR (CDCl₃)δ: 2.44 (1H, dd, J=13.6, 10.2 Hz), 2.87(1H, dd, J=13.6, 2.6 Hz), 3.22-3.36 (1H, m), 4.64 (1H, d, J=5.2 Hz),6.96-7.16 (4H, m), 7.30-7.42 (2H, m), 7.44-7.58 (1H, m).

8) To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-fluoro-4-(trifluoromethyl)phenyl)-1-propanol(400 mg, 1.21 mmol) in acetonitrile (30 ml) were added4-fluoronaphthalenecarboxylic acid (230 mg, 1.21 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (347 mg,1.81 mmol) and 1-hydroxy-1H-benzotriazole (185 mg, 1.21 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to give the titlecompound (525 mg, 86%).

mp 212-213° C. IR ν max^(KBr)cm⁻¹: 1640, 1626, 1599, 1514, 1435, 1325.Anal. Calcd for C₂₇H₁₉F₆NO₂.0.1H₂O: C, 64.19; H, 3.83; N, 2.77. Found:C, 63.97; H, 3.83; N, 2.52. ¹H-NMR (CDCl₃)δ: 2.82-3.16 (3H, m),4.70-4.90 (1H, m), 5.12 (1H, d, J=3.6 Hz), 6.05 (1H, d, J=8.8 Hz),7.00-7.30 (6H, m), 7.40-7.62 (5H, m), 7.72 (1H, d, J=8.0 Hz), 8.11 (1H,d, J=7.8 Hz).

Example 157N-((1RS,2SR)-2-(4-fluorophenyl)-1-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-hydroxyethyl)-3-phenylpropanamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-fluoro-4-(trifluoromethyl)phenyl)-1-propanol(400 mg, 1.21 mmol) in ethyl acetate (20 ml) were added3-phenylpropionyl chloride (269 ml, 1.81 mmol) and saturated aqueoussodium hydrogen carbonate (20 ml) and the mixture was stirred overnightat room temperature. The reaction solution was diluted with water (100ml) and extracted with ethyl acetate (100 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the title compound (486 mg, 87%).

mp 126-127° C. IR ν max^(KBr)cm⁻¹: 1632, 1510, 1435, 1325. Anal. Calcdfor C₂₅H₂₂F₅NO₂: C, 64.79; H, 4.78; N, 3.02. Found: C, 64.61; H, 4.77;N, 2.80. ¹H-NMR (CDCl₃)δ: 2.32-2.44 (2H, m), 2.58-2.80 (2H, m), 2.88(2H, t, J=7.4 Hz), 3.00 (1H, d, J=4.2 Hz), 4.26-4.42 (1H, m), 4.76-4.84(1H, m), 5.38 (1H, d, J=8.4 Hz), 6.78-6.90 (2H, m), 7.00-7.50 (10H, m).

Example 1584-fluoro-N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(phenyloxy)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

1) To a solution of 4-(phenyloxy)benzoic acid (10.4 g, 48.7 mmol) intetrahydrofuran (30 ml) was added 1M tetrahydrofuran solution of borane(63 ml, 63 mmol) at room temperature and the mixture was stirredovernight. 1N Hydrochloric acid was added to the reaction solution forquenching and the mixture was extracted with ethyl acetate (100 ml×2).The extract was washed successively with water and saturated brine,dried over anhydrous magnesium sulfate and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate) and recrystallized from hexane to give(4-(phenyloxy)phenyl)methanol (8.51 g, 87%).

mp 48-49° C. IR ν max^(KBr)cm⁻¹: 1590, 1507, 1489, 1240. Anal. Calcd forC₁₃H₁₂O₂: C, 77.98; H, 6.04. Found: C, 77.94; H, 5.74. ¹H-NMR (CDCl₃)δ:1.67 (1H, brs), 4.67 (2H, d, J=4.0 Hz), 6.96-7.18 (5H, m), 7.22-7.40(4H, m).

2) To a solution of (4-(phenyloxy)phenyl)methanol (8 g, 40.0 mmol) inchloroform (20 ml) was added thionyl chloride (36 ml, 500 mmol) and themixture was heated under reflux overnight. The reaction solution wasconcentrated. The residue was purified by silica gel columnchromatography (ethyl acetate) to give1-(chloromethyl)-4-(phenyloxy)benzene (8.1 g, 93%).

IR ν max^(KBr)cm⁻¹: 1590, 1507, 1489, 1240. ¹H-NMR (CDCl₃)δ: 3.93 (1H,brs), 4.57 (2H, s), 6.80-7.40 (9H, m).

3) To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (6.49 g,30.9 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60%in oil, 1.23 g, 30.9 mmol) under ice-cooling and the mixture was stirredat room temperature for 30 min. To the reaction solution was dropwiseadded a solution of 1-(chloromethyl)-4-(phenyloxy)benzene (8.1 g, 37.0mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution washeated under reflux overnight. The reaction solution was poured intowater (200 ml) and extracted with ethyl acetate (200 ml×2). The extractwas washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography(toluene:hexane=1:1-toluene) to give ethyl3-(4-fluorophenyl)-3-oxo-2-((4-(phenyloxy)phenyl)methyl)propionate (7.76g, crude, 64%).

¹H-NMR (CDCl₃)δ: 1.14 (3H, t, J=7.4 Hz), 3.30 (2H, d, J=7.6 Hz), 4.12(2H, q, J=7.4 Hz), 4.56 (1H, t, J=7.6 Hz), 6.80-7.40 (11H, m), 7.90-8.08(2H, m).

4) To a solution of zinc chloride (5.39 g, 39.6 mmol) in diethyl ether(100 ml) was added sodium borohydride (3.00 g, 79.1 mmol) and themixture was stirred at room temperature for 30 min. The insolublematerial was filtered off. To the filtrate was added a solution of ethyl3-(4-fluorophenyl)-3-oxo-2-((4-(phenyloxy)phenyl)methyl)propionate (7.76g, 19.8 mmol) in diethyl ether (50 ml) and the mixture was stirred atroom temperature for 30 min. 1N Hydrochloric acid was added to thereaction solution under ice-cooling for quenching, water (200 ml) wasadded, and the mixture was extracted with ethyl acetate (300 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethylacetate=4:1-1:1) to give ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-(phenyloxy)phenyl)methyl)propionate(6.66 g, 85%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1726, 1590, 1507, 1489. ¹H-NMR (CDCl₃)δ: 0.97 (3H,t, J=7.0 Hz), 2.90-3.00 (4H, m), 3.91 (2H, q, J=7.0 Hz), 5.00 (1H, brs),6.82-7.20 (9H, m), 7.24-7.42 (4H, m).

5) To a solution of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-(phenyloxy)phenyl)methyl)propionate(6.6 g, 16.7 mmol) in methanol (30 ml) was added 2N aqueous sodiumhydroxide solution (16.7 ml, 33.4 mmol) and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=1:1)to give(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-(phenyloxy)phenyl)methyl)propionicacid (5.8 g, 95%).

IR ν max^(KBr)cm⁻¹: 1713, 1590. Anal. Calcd for C₂₂H₁₉FO₄: C, 72.12; H,5.23. Found: C, 72.20; H, 5.23. ¹H-NMR (CDCl₃)δ: 2.90-3.08 (3H, m), 3.92(1H, s), 5.05 (1H, d, J=4.4 Hz), 6.80-7.20 (9H, m), 7.30-7.44 (4H, m).

6) To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-(phenyloxy)phenyl)methyl)propionicacid (5.5 g, 15.0 mmol) in tetrahydrofuran (150 ml) were addeddiphenylphosphoryl azide (3.56 ml, 16.5 mmol)-and triethylamine (3.15ml, 22.5 mmol) and the mixture was heated under reflux for 4 hrs. Thereaction solution was allowed to stand at room temperature, water (200ml) was added, and the mixture was extracted with ethyl acetate (200ml×2). The extract was washed successively with 1N hydrochloric acid,saturated aqueous sodium hydrogen carbonate and saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1-1:1) and recrystallized from ethylacetate-hexane to give(4RS,5SR)-5-(4-fluorophenyl)-4-((4-(phenyloxy)phenyl)methyl)-1,3-oxazolidin-2-one(3.74 g, 69%).

mp 144-145° C. IR ν max^(KBr)cm⁻¹: 1755, 1590, 1505. ¹H-NMR (CDCl₃)δ:2.16-2.30 (2H, m), 4.16-4.30 (1H, m), 5.14 (1H, s), 5.79 (1H, d, J=8.0Hz), 6.80-7.42 (13H, m).

7) To a solution of(4RS,5SR)-5-(4-fluorophenyl)-4-((4-(phenyloxy)phenyl)methyl)-1,3-oxazolidin-2-one(2.5 g, 6.88 mmol) in ethanol (20 ml) was added 8N aqueous sodiumhydroxide solution (4.30 ml, 34.4 mmol) and the mixture was heated underreflux for 6 hrs. The reaction solution was concentrated, diluted withwater (100 ml) and extracted with ethyl acetate (100 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure to give(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(phenyloxy)phenyl)-1-propanol(2.2 g, 95%).

Ir ν max^(KBr)cm⁻¹: 1590, 1507, 1489, 1238. ¹H-NMR (CDCl₃)δ: 2.00-2.40(2H, m), 3.93 (1H, s), 5.11 (1H, d, J=7.4 Hz), 6.80-7.40 (13H, m).

8) To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(phenyloxy)phenyl)-1-propanol(353 mg, 1.05 mmol) in acetonitrile (20 ml) were added4-fluoronaphthalenecarboxylic acid (200 mg, 1.05 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (302 mg,1.58 mmol) and 1-hydroxy-1H-benzotriazole (161 mg, 1.05 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1-1:1). Recrystallization from ethyl acetate-hexane gave thetitle compound (166 mg, 31%).

mp 104-105° C. IR ν max^(KBr)cm⁻¹: 1644, 1626, 1601, 1590, 1507, 1489.¹H-NMR (CDCl₃)δ: 2.75 (1H, dd, J=14.4, 11.0 Hz), 3.06 (1H, dd, J=14.4,4.0 Hz), 3.64-3.70 (1H, m), 4.70-4.88 (1H, m), 5.04-5.12 (1H, m), 5.90(1H, d, J=8.4 Hz), 6.90-7.60 (17H, m), 7.78-7.86 (1H, m), 8.09 (1H, d,J=7.8 Hz).

Example 159N-(1RS,2SR)-(2-(4-fluorophenyl)-2-hydroxy-1-((4-(phenyloxy)phenyl)methyl)ethyl)-3-phenylpropanamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(phenyloxy)phenyl)-1-propanol(550 mg, 1.63 mmol) in ethyl acetate (20 ml) were added3-phenylpropionyl chloride (360 ml, 2.45 mmol) and saturated aqueoussodium hydrogen carbonate (20 ml) and the mixture was stirred overnightat room temperature. The reaction solution was diluted with water (100ml) and extracted with ethyl acetate (100 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1-1:1) andrecrystallized from ethyl acetate-hexane to give the title compound (152mg, 20%).

mp 108-110° C. IR ν max^(KBr)cm⁻¹: 1644, 1605, 1507, 1489. ¹H-NMR(CDCl₃)δ: 2.24-2.40 (2H, m), 2.40-3.00 (5H, m), 4.30-4.44 (1H, m),4.76-4.84 (1H, m), 5.69 (1H, d, J=8.0 Hz), 6.80-7.36 (18H, m).

Example 1604-fluoro-N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((3-(phenyloxy)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

1) To a solution of (3-(phenyloxy)phenyl)methanol (10 g, 49.4 mmol) inchloroform (20 ml) was added thionyl chloride (36 ml, 500 mmol) and themixture was heated under reflux overnight. The reaction solution wasconcentrated. The residue was purified by silica gel columnchromatography (ethyl acetate) to give1-(chloromethyl)-3-(phenyloxy)benzene (10.7 g, 98%).

IR ν max^(KBr)cm⁻¹: 1584, 1487, 1445. ¹H-NMR (CDCl₃)δ: 4.53 (2H, s),6.80-7.40 (9H, m).

2) To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (7.2 g,34.3 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60%in oil, 1.37 g, 34.3 mmol) under ice-cooling and the mixture was stirredat room temperature for 30 min. To the reaction solution was dropwiseadded a solution of 1-(chloromethyl)-3-(phenyloxy)benzene (9.0 g, 41.6mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution washeated under reflux overnight. The reaction solution was poured intowater (200 ml) and extracted with ethyl acetate (200 ml×2). The extractwas washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography(toluene:hexane=1:1-toluene) to give ethyl3-(4-fluorophenyl)-3-oxo-2-((3-(phenyloxy)phenyl)methyl)propionate (10.2g, crude, 76%).

¹H-NMR (CDCl₃)δ: 1.12 (3H, t, J=7.0 Hz), 3.29 (2H, d, J=7.2 Hz), 4.09(2H, q, J=7.0 Hz), 4.55 (1H, t, J=7.2 Hz), 6.70-7.40 (11H, m), 7.90-8.04(2H, m).

3) To a solution of zinc chloride (7.08 g, 51.9 mmol) in diethyl ether(100 ml) was added sodium borohydride (3.93 g, 103.9 mmol) and themixture was stirred at room temperature for 30 min. The insolublematerial was filtered off. To the filtrate was added a solution of ethyl3-(4-fluorophenyl)-3-oxo-2-((3-(phenyloxy)phenyl)methyl)propionate (10.2g, 26.0 mmol) in diethyl ether (50 ml) and the mixture was stirred atroom temperature for 30 min. 1N Hydrochloric acid was added to thereaction solution under ice-cooling for quenching, water (200 ml) wasfurther added, and the mixture was extracted with ethyl acetate (300ml×2). The extract was washed with water and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethyl acetate)to give ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(phenyloxy)phenyl)methyl)propionate(5.26 g, 51%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1728, 1715, 1582, 1487. ¹H-NMR (CDCl₃)δ: 0.96 (3H,t, J=7.2 Hz), 2.82-3.04 (4H, m), 3.89 (2H, q, J=7.2 Hz), 5.00 (1H, brs),6.78-7.40 (13H, m).

4) To a solution of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(phenyloxy)phenyl)methyl)propionate(5.26 g, 13.3 mmol) in methanol (40 ml) was added 2N aqueous sodiumhydroxide solution (13.4 ml, 26.8 mmol) and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). Theextract was washed with water and saturated-brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=1:1)to give(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(phenyloxy)phenyl)methyl)propionicacid (2.31 g, 47%).

IR ν max^(KBr)cm⁻¹: 1713, 1584, 1510, 1487. ¹H-NMR (CDCl₃)δ: 2.84-3.06(4H, m), 5.04 (1H, d, J=4.4 Hz), 6.76-7.40 (13H, m).

5) To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(phenyloxy)phenyl)methyl)propionicacid (2.2 g, 6.00 mmol) in tetrahydrofuran (60 ml) were addeddiphenylphosphoryl azide (1.42 ml, 6.60 mmol) and triethylamine (1.26ml, 9.00 mmol) and the mixture was heated under reflux for 4 hrs. Thereaction solution was allowed to stand at room temperature, water (200ml) was added, and the mixture was extracted with ethyl acetate (200ml×2). The extract was washed successively with 1N hydrochloric acid,saturated aqueous sodium hydrogen carbonate and saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1-1:1) to give(4RS,5SR)-5-(4-fluorophenyl)-4-((3-(phenyloxy)phenyl)methyl)-1,3-oxazolidin-2-one(1.69 g, 77%).

Ir ν max^(KBr)cm⁻¹: 1759, 1608, 1584. ¹H-NMR (CDCl₃)δ: 2.10-2.32 (2H,m), 4.16-4.30 (1H, m), 5.13 (1H, s), 5.77 (1H, d, J=7.8 Hz), 6.60-7.40(13H, m).

6) To a solution of(4RS,5SR)-5-(4-fluorophenyl)-4-((3-(phenyloxy)phenyl)methyl)-1,3-oxazolidin-2-one(877 mg, 2.41 mmol) in ethanol (10 ml) was added 8N aqueous sodiumhydroxide solution (1.51 ml, 12.1 mmol) and the mixture was heated underreflux for 6 hrs. The reaction solution was concentrated, diluted withwater (100 ml) and extracted with ethyl acetate (10.0 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure to give(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(phenyloxy)phenyl)-1-propanol(831 mg, 100%).

IR ν max^(KBr)cm⁻¹: 1582, 1507, 1487, 1445. ¹H-NMR (CDCl₃)δ: 2.31 (1H,dd, J=13.6, 10.2 Hz), 2.75 (1H, dd, J=13.6, 3.0 Hz), 3.18-3.36 (1H, m),4.65 (1H, d, J=4.6 Hz), 6.78-7.40 (13H, m).

7) To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(phenyloxy)phenyl)-1-propanol(300 mg, 0.89 mmol) in acetonitrile (20 ml) were added4-fluoronaphthalenecarboxylic acid (169 mg, 0.89 mmol),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (256 mg,1.33 mmol) and 1-hydroxy-1H-benzotriazole (136 mg, 0.89 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1-1:1). Recrystallization from ethyl acetate-hexane gave thetitle compound (148 mg, 33%).

mp 120-121° C. IR ν max^(KBr)cm⁻¹: 1642, 1626, 1601, 1584. Anal. Calcdfor C₃₂H₂₅F₂NO₃: C, 75.43; H, 4.95; N, 2.75. Found: C, 75.33; H, 5.05;N, 2.54. ¹H-NMR (CDCl₃)δ: 2.73 (1H, dd, J=14.4, 10.6 Hz), 3.02 (1H, dd,J=14.4, 4.0 Hz), 3.60-3.64 (1H, m), 4.66-4.82 (1H, m), 5.04-5.12 (1H,m), 5.87 (1H, d, J=8.4 Hz), 6.80-7.36 (13H, m), 7.38-7.62 (4H, m), 7.81(1H, d, J=8.0 Hz), 8.09 (1H, d, J=7.8 Hz).

Example 161N-(1RS,2SR)-(2-(4-fluorophenyl)-2-hydroxy-1-((3-(phenyloxy)phenyl)methyl)ethyl)-3-phenylpropanamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(phenyloxy)phenyl)-1-propanol(550 mg, 1.63 mmol) in ethyl acetate (20 ml) were added3-phenylpropionyl chloride (360 ml, 2.45 mmol) and saturated aqueoussodium hydrogen carbonate (20 ml) and the mixture was stirred overnightat room temperature. The reaction solution was diluted with water (100ml) and extracted with ethyl acetate (100 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1-1:1) andrecrystallized from ethyl acetate-hexane to give the title compound (422mg, 55%).

mp 91-93° C. IR ν max^(KBr)cm⁻¹: 1645, 1584, 1510, 1487, 1447. ¹H-NMR(CDCl₃)δ: 2.22-2.90 (6H, m), 4.22-4.42 (1H, m), 4.81 (1H, s), 5.30 (1H,d, J=8.2 Hz), 6.62-7.40 (18H, m).

Example 162 1,1-dimethylethyl(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((5-(trifluoromethyl)-2-furanyl)methyl)ethylcarbamate

1) To a solution of ethyl trifluoroacetate (75 g, 407 mmol) in1,2-dimethoxyethane (200 ml) was added sodium hydride (60% in oil, 16.3g, 407 mmol) under ice-cooling and the mixture was stirred at roomtemperature for 30 min. To the reaction solution was dropwise added asolution of chloroacetone (43.3 g, 469 mmol) in 1,2-dimethoxyethane (50ml) and potassium iodide (800 mg, 4.8 mmol) was further added. Thereaction solution was heated under reflux overnight. The reactionsolution was poured into water (500 ml) and extracted with diethyl ether(500 ml×2). The extract was washed with water and saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was distilled under reduced pressure to give ethyl4-oxo-2-(2,2,2-trifluoroacetyl)valerate (40.5 g, 41%).

IR ν max^(KBr)cm⁻¹: 1742, 1723. ¹H-NMR (CDCl₃)δ: 1.28 (3H, t, J=7.0 Hz),2.22 (3H, s), 3.26 (2H, d, J=7.0 Hz), 4.10-4.50 (3H, m). bp 110-125°C./0.1 mmHg

2) To a solution of ethyl 4-oxo-2-(2,2,2-trifluoroacetyl)valerate (40 g,167 mmol) in toluene (250 ml) was added p-toluenesulfonic acid (3 g, 16mmol) and the mixture was heated under reflux overnight in a Dean-Starkapparatus under dehydrated conditions. The reaction solution wasconcentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=10:1) to give ethyl5-methyl-2-(trifluoromethyl)-3-furancarboxylate (25.8 g, 70%).

IR ν max^(KBr)cm⁻¹: 1732, 1574. ¹H-NMR (CDCl₃)δ: 1.35 (3H, t, J=7.4 Hz),2.35 (3H, s), 4.32 (2H, q, J=7.4 Hz), 4.62 (1H, s).

3) To a solution of ethyl5-methyl-2-(trifluoromethyl)-3-furancarboxylate (25 g, 113 mmol) inethanol (200 ml) was added 2N aqueous sodium hydroxide solution (61.9ml, 123.8 mmol) and the mixture was heated under reflux for 45 min. Thereaction solution was concentrated, diluted with water (150 ml), and 6Nhydrochloric acid was gradually added to adjust to about pH 5. Theprecipitated crystals were collected by filtration, washed with water togive 5-methyl-2-(trifluoromethyl)-3-furancarboxylic acid (20.5 g, 94%).

IR ν max^(KBr)cm⁻¹: 1711, 1574. mp 118-119° C. ¹H-NMR (CDCl₃)δ: 2.38(3H, s), 6.52 (1H, s).

4) To a solution of 5-methyl-2-(trifluoromethyl)-3-furancarboxylic acid(20 g, 103 mmol) in quinoline (36 ml) was added copper (I) sulfate (1 g,6.3 mmol). While bubbling nitrogen, the mixture was immersed in an oilbath at 230° C. until gas generation ceased. The generated gas wascollected and distilled again to give 2-methyl-5-(trifluoromethyl)furan(8.34 g, 54%).

¹H-NMR (CDCl₃)δ: 2.34 (3H, s), 6.05 (1H, d, J=3.4 Hz), 6.60 (1H, d,J=2.2 Hz). bp 80-85° C./760 mmHg (Lit. 81-82° C., J. Hetrocyclic Chem.,5, 95 (1968))

5) To a solution of 2-methyl-5-(trifluoromethyl)furan (4 g, 26.6 mmol)in chloroform (60 ml) were added N-bromosuccinimide (5.2 g, 29.3 mmol)and 2,2′-azobis(isobutyronitrile) (220 mg, 1.33 mmol). The reactionsolution was heated under reflux for 15 min. The reaction solution wascooled, poured into water (200 ml) and was extracted with chloroform.The extract was washed with water and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure togive 2-(bromomethyl)-5-(trifluoromethyl)furan (4.79 g, 78%).

Ir ν max^(KBr)cm⁻¹: 1738, 1688, 1599, 1559. ¹H-NMR (CDCl₃)δ: 4.46 (2H,s), 6.45 (1H, d, J=3.8 Hz), 6.75 (1H, d, J=3.8 Hz).

6) To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (5.0 g, 24mmol) in 1,2-dimethoxyethane (40 ml) was added sodium hydride (60% inoil, 576 mg, 24 mmol) under ice-cooling and the mixture was stirred atroom temperature for 1 hr. To the reaction solution was dropwise added asolution of. 2-(bromomethyl)-5-(trifluoromethyl)furan (6 g, 26 mmol) in1,2-dimethoxyethane (50 ml) and the reaction solution was stirredovernight at room temperature. The reaction solution was poured intowater (200 ml), saturated aqueous sodium hydrogen carbonate was added,and the mixture was extracted with ethyl acetate (200 ml×2). The extractwas washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=4:1)to give ethyl3-(4-fluorophenyl)-3-oxo-2-((5-(trifluoromethyl)-2-furanyl)methyl)propionate(4.5 g, 52%).

IR ν max^(KBr)cm⁻¹: 1738, 1688, 1599, 1559. ¹H-NMR (CDCl₃)δ: 1.16 (3H,t, J=7.2. Hz), 3.14-3.50 (2H, m), 4.14 (2H, q, J=7.2 Hz), 4.73 (1H, t,J=7.4 Hz), 6.15 (1H, d, J=4.0 Hz), 6.60-6.66 (1H, m), 7.08-7.30 (3H, m),7.98-8.10 (2H, m).

7) To a solution of zinc chloride (3.35 g, 24.6 mmol) in diethyl ether(70 ml) was added sodium borohydride (1.86 g, 49.1 mmol) and the mixturewas stirred at room temperature for 30 min. The insoluble material wasfiltered off. To the filtrate was added a solution of ethyl3-(4-fluorophenyl)-3-oxo-2-((5-(trifluoromethyl)-2-furanyl)methyl)propionate(4.40 g, 12.3 mmol) in diethyl ether (30 ml) and the mixture was stirredat room temperature for 2 hrs. 1N Hydrochloric acid was added to thereaction solution under ice-cooling for quenching, water (100 ml) wasfurther added, and the mixture as extracted with ethyl acetate (100ml×2). The extract was washed with water and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1) to give ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((5-(trifluoromethyl)-2-furanyl)methyl)propionate(3.46 g, 78%).

IR ν max^(KBr)cm⁻¹: 1717, 1607, 1561. ¹H-NMR (CDCl₃)δ: 1.06 (3H, t,J=7.0 Hz), 2.90-3.22 (4H, m), 4.00 (2H, q, J=7.0 Hz), 5.00-5.08 (1H, m),6.05 (1H, d, J=3.4 Hz), 6.58-6.64 (1H, m), 6.98-7.10 (2H, m), 7.30-7.42(2H, m).

8) To a solution of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((5-(trifluoromethyl)-2-furanyl)methyl)propionate(3.3 g, 9.16 mmol) in methanol (9.2 ml) was added 2N aqueous sodiumhydroxide solution (9.2 ml,18.4 mmol) and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid and extracted with ethyl acetate (100 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from diisopropyl ether-hexane to give(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((5-(trifluoromethyl)-2-furanyl)methyl)propionicacid (2.43 g, 80%).

IR ν max^(KBr)cm⁻¹: 1715, 1563, 1513. mp 86-87° C. ¹H-NMR (CDCl₃)δ:2.92-3.22 (3H, m), 5.13 (1H, d, J=4.0 Hz), 6.06 (1H, d, J=3.2 Hz),6.60-6.68 (1H, m), 7.00-7.16 (2H, m), 7.30-7.44 (2H, m).

9) To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((5-(trifluoromethyl)-2-furanyl)methyl)propionicacid (2.33 g, 7.01 mmol) in tetrahydrofuran (60 ml) were addeddiphenylphosphoryl azide (1.66 ml, 7.71 mmol) and triethylamine (1.47ml, 10.5 mmol) and the mixture was heated under reflux for 4 hrs. Thereaction solution was allowed to stand at room temperature, water (50ml) was added, and the mixture was extracted with ethyl acetate (100ml×2). The extract was washed successively with water and saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate) and recrystallized from ethylacetate-hexane to give(4RS,5SR)-5-(4-fluorophenyl)-4-((5-(trifluoromethyl)-2-furanyl)methyl)-1,3-oxazolidine-2-one(1.78 mg, 77%).

IR ν max^(KBr)cm⁻¹: 1759, 1611, 1559, 1514. mp 177-179° C. ¹H-NMR(CDCl₃)δ: 2.30-2.58 (2H, m), 4.32-4.50 (1H, m), 5.67 (1H, brs), 5.80(1H, d, J=8.0 Hz), 6.00 (1H, d, J=3.6 Hz), 6.65 (1H, d, J=2.2 Hz),7.02-7.20 (2H, m), 7.24-7.40 (2H, m).

10) To a solution of(4RS,5SR)-5-(4-fluorophenyl)-4-((5-(trifluoromethyl)-2-furanyl)methyl)-1,3-oxazolidine-2-one(1.60 g, 4.86 mmol) in acetonitrile (15 ml) were added di-t-butyldicarbonate (1.27 g, 5.83 mmol) and dimethylaminopyridine (60 mg, 0.49mmol) and the mixture was stirred at room temperature for 30 min. Thereaction solution was concentrated, diluted with water (30 ml) andextracted with ethyl acetate (30 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:1) and recrystallized from ethylacetate-hexane to give 1,1-dimethylethyl(4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-((5-(trifluoromethyl)-2-furanyl)methyl)-1,3-oxazolidine-3-carboxylate(1.99 g, 95%).

IR ν max^(KBr)cm⁻¹: 1823, 1728, 1615, 1559. mp 134-135° C. ¹H-NMR(CDCl₃)δ: 1.55 (9H, s), 2.70-2.98 (2H, m), 4.86-4.98 (1H, m), 5.52 (1H,d, J=3.2 Hz), 5.70 (1H, d, J=7.0 Hz), 6.46-6.52 (1H, m), 6.94-7.06 (2H,m), 7.12-7.22 (2H, m).

11) To 1,1-dimethylethyl(4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-((5-(trifluoromethyl)-2-furanyl)methyl)-1,3-oxazolidine-3-carboxylate(1.91 g, 4.45 mmol) in methanol (10.7 ml) was added a methanol solution(10.7 ml, 5.35 mmol) of 0.5N sodium hydroxide under ice-cooling and themixture was stirred at room temperature for 10 min. Water (50 ml) wasadded to the reaction solution and the mixture was extracted with ethylacetate (50 ml×2). The extract was washed with saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was recrystallized from ethyl acetate-hexane to give thetitle compound (1.79 g, 100%).

IR ν max^(KBr)cm⁻¹: 1692, 1561, 1510. mp 111-112° C. ¹H-NMR (CDCl₃)δ:1.39 (9H, s), 2.78-2.90 (2H, m), 3.12 (1H, brs), 4.02-4.20 (1H, m), 4.76(1H, d, J=8.4 Hz), 4.92 (1H, brs), 6.12 (1H, d, J=3.0 Hz), 6.62-6.68(1H, m), 7.00-7.12 (2H, m), 7.28-7.42 (2H, m).

Example 1634-fluoro-N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((5-(trifluoromethyl)-2-furanyl)methyl)ethyl)-1-naphthalenecarboxamide

1) To 1,1-dimethylethyl(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((5-(trifluoromethyl)-2-furanyl)methyl)ethylcarbamate(1.70 g, 4.21 mmol) was added trifluoroacetic acid (15 ml) at 0° C. andthe mixture was stirred for 10 min. The reaction solution wasconcentrated, diluted with water (20 ml) and extracted with ethylacetate (20 ml×2). The extract was washed with saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was recrystallized from diisopropyl ether-hexane to give(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(5-(trifluoromethyl)-2-furanyl)-1-propanol(1.30 g, 100%).

IR ν max^(KBr)cm⁻¹: 1605, 1558, 1510. ¹H-NMR (CDCl₃)δ: 2.07 (2H, brs),2.56 (1H, dd, J=15.0, 9.8 Hz), 2.78 (1H, dd, J=15.0, 3.6 Hz), 3.32-3.46(1H, m), 4.66 (1H, d, J=4.8 Hz), 6.12 (1H, d, J=3.4 Hz), 6.62-6.70 (1H,m), 7.00-7.12 (2H, m), 7.30-7.42 (2H, m).

2) To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(5-(trifluoromethyl)-2-furanyl)-1-propanol(300 mg, 0.99 mmol) in acetonitrile (20 ml) were added4-fluoronaphthalenecarboxylic acid (188 mg, 0.99 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (283 mg,1.48 mmol) and 1-hydroxy-1H-benzotriazole (151 mg, 0.99 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with water and saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1). Recrystallization from ethylacetate-hexane gave the title compound (191 mg, 41%).

IR ν max^(KBr)cm⁻¹: 1643, 1601, 1512. mp 153-154° C. ¹H-NMR (CDCl₃)δ:3.54 (2H, d, J=7.4 Hz), 3.23 (1H, d, J=3.4 Hz), 4.68-4.86 (1H, m),5.06-5.12 (1H, m), 6.12-6.28 (2H, m), 6.72 (1H, d, J=2.2 Hz), 7.00-7.16(3H, m), 7.32-7.62 (5H, m), 8.00-8.20 (2H, m).

Example 164N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((5-(trifluoromethyl)-2-furanyl)methyl)ethyl)-3-phenylpropanamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(5-(trifluoromethyl)-2-furanyl)-1-propanol(300 mg, 099 mmol) in ethyl acetate (10 ml) were added 3-phenylpropionylchloride (220 ml, 1.48 mmol) and saturated aqueous sodium hydrogencarbonate (10 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (100 ml) andextracted with ethyl acetate (100 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was recrystallized from ethylacetate-hexane to give the title compound (321 mg, 75%).

IR ν max^(HBr)cm⁻¹: 1645, 1559, 1510. mp 91-92° C. ¹H-NMR (CDCl₃)δ:2.32-2.60 (2H, m), 2.73 (2H, d, J=7.6 Hz), 2.80-3.00 (2H, m), 3.10 (1H,s), 4.30-4.48 (1H, m), 4.76-4.84 (1H, m), 5.58 (1H, d, J=7.6 Hz), 6.00(1H, d, J=3.4 Hz), 6.58-6.64 (1H, m), 6.92-7.10 (2H, m), 7.10-7.36 (7H,m).

Example 165N-[(1RS,2SR)-1-[4-(difluoromethyl)benzyl]-2-(4-fluorophenyl)-2-hydroxyethyl]-4-fluoronaphthalene-1-carboxamide

1) methyl 4-(difluoromethyl)benzoate

To a solution of (diethylamino)sulfur trifluoride (12.8 g, 79.4 mmol) intoluene (30 ml) was added a solution of methyl 4-formylbenzoate (10.86g, 66.15 mmol) in toluene (50 ml) at −78° C. and the mixture was stirredat room temperature for 3 hrs. Aqueous sodium hydrogen carbonatesolution was added to the reaction solution. The mixture was stirred andthe toluene layer was separated. The aqueous layer was extracted withethyl acetate. The collected organic layer was dried over anhydrousmagnesium sulfate and the solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography(hexane/ethyl acetate=20/1-15/1) to give the objective substance.

pale-yellow solid yield 9.671 g, 79% mp 37-38° C.; ¹H-NMR (CDCl₃, 200MHz) δ 3.95 (3H, s), 6.69 (1H, t, J=56.2 Hz), 7.59 (2H, d, J=8.2 Hz),8.13 (2H, d, J=8.4 Hz); IR (neat) 1728, 1437, 1283, 1219, 1113, 1074,1034, 1020 cm⁻¹; Anal. Calcd for C₉H₈F₂O₂: C, 58.07; H, 4.33. Found: C,58.31; H, 4.24.

2) 4-(difluoromethyl)benzyl alcohol

To a suspension of lithium aluminum hydride (2.86 g, 75.3 mmol) intetrahydrofuran (50 ml) was dropwise added a solution of methyl4-(difluoromethyl)benzoate (9.341 g, 50.18 mmol) in tetrahydrofuran (50ml) under ice-cooling and the mixture was stirred at room temperaturefor 1 hr. The reaction solution was ice-cooled and water (3 ml), 15%aqueous sodium hydroxide solution (3 ml) and water (8 ml) were dropwiseadded successively to decompose excess lithium aluminum hydride. Themixture was stirred as it was at room temperature for 2 hrs. Theresulting precipitate was removed by filtration and the precipitate waswashed with ethyl acetate. The solvent of the collected filtrate wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (hexane/ethyl acetate=3/1-1/1) to givethe objective-substance.

colorless liquid yield 7.948 g, 100% ¹H-NMR (CDCl₃, 200 MHz) δ 1.78 (1H,t, J=6.0 Hz), 4.76 (2H, d, J=5.4 Hz), 6.65 (1H, t, J=56.4 Hz), 7.45 (2H,d, J=8.6 Hz), 7.52 (2H, d, J=8.6 Hz); IR (neat) 3330, 1379, 1221, 1074,1019 cm⁻¹

3) ethyl 2-[4-(difluoromethyl)benzyl]-3-(4-fluorophenyl)-3-oxopropionate

To a solution of 4-(difluoromethyl)benzyl alcohol (2.65 g, 16.7 mmol)and triethylamine (3.50 ml, 25.1 mmol) in ethyl acetate (40 ml) wasdropwise added a solution of methanesulfonyl chloride (2.11 g, 18.4mmol) in ethyl acetate (10 ml) under ice-cooling and the mixture wasstirred as it was for 10 min. The resulting precipitate was removed byfiltration and the precipitate was washed with diethyl ether. Thesolvent of the collected filtrate was evaporated under reduced pressureto give a crude product of the methanesulfonic acid ester as a yellowliquid.

To a solution of ethyl (4-fluorobenzoyl)acetate (3.516 g, 16.73 mmol) in1,2-dimethoxyethane (30 ml) was added a suspension (0.67 g, 16.7 mmol)of60% sodium hydride in liquid paraffin under ice-cooling and the mixturewas stirred as it was for 0.5 hr. A solution of the methanesulfonic acidester obtained above in 1,2-dimethoxyethane (10 ml) was added thereto atroom temperature and the mixture was stirred at room temperature for 8hrs. The reaction solution was poured into water and extracted twicewith ethyl acetate. The collected organic layer was dried over anhydrousmagnesium sulfate and the solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography(hexane/ethyl acetate=15/1-9/1) and crystallized from hexane to give theobjective substance.

white crystal yield 3.044 g, 52% mp 54-55° C.; ¹H-NMR (CDCl₃, 200 MHz) δ1.11 (3H, t, J=7.2 Hz), 3.36 (2H, d, J=7.4 Hz), 4.10 (2H, q, J=7.2 Hz),4.57 (1H, t, J=7.5 Hz), 6.59 (1H, t, J=56.4 Hz), 7.12 (2H, t, J=8.6 Hz),7.31 (2H, d, J=8.4 Hz), 7.41 (2H, d, J=7.8 Hz), 8.00 (2H, dd, J=5.4 Hz,8.8 Hz); IR (KBr) 1721, 1684, 1597, 1327, 1281, 1231, 1177, 1155, 1024,847 cm⁻¹; Anal. Calcd for C₁₉H₁₇F₃O₃: C, 65.14; H, 4.89. Found: C,65.21; H, 4.82.

4) ethyl(2RS,3RS)-2-[4-(difluoromethyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionate

While stirring zinc chloride (2.17 g, 16.0 mmol) in diethyl ether (50ml), sodium borohydride (1.21 g, 31.9 mmol) as added at room temperatureand the mixture was stirred as it was for 2 hrs. The insoluble materialof the mixture was removed by filtration (washed with diethyl ether) togive a solution of zinc borohydride in diethyl ether. To the obtainedsolution was added a solution of ethyl2-[4-(difluoromethyl)benzyl]-3-(4-fluorophenyl)-3-oxopropionate (2.794g, 7.975 mmol) in diethyl ether (30 ml) at room temperature and themixture was stirred as it was for 2 hrs. To the reaction solution wasadded dilute hydrochloric acid by small portions to decompose excesszinc borohydride and the mixture was extracted twice with ethyl acetate.The collected organic layer was dried over anhydrous magnesium sulfateand the solvent was evaporated under reduced pressure. The obtainedcrude product was purified by silica gel column chromatography(hexane/ethyl acetate=6/1−3/1) to give the objective substance.

colorless liquid yield 2.800 g, 100% ¹H-NMR (CDCl₃, 200 MHz) δ 0.92 (3H,t, J=7.1 Hz), 2.90 (1H, d, J=2.8 Hz), 2.93-3.06 (3H, m), 3.88 (2H, q,J=7.2 Hz), 5.02 (1H, dd, J=2.6 Hz, 4.6 Hz), 6.59 (1H, t, J=56.6 Hz),7.05 (2H, t, J=8.6 Hz), 7.17 (2H, d, J=8.0 Hz), 7.34-7.41 (4H, m); IR(neat) 3445, 1725, 1715, 1510, 1377, 1223, 1026, 839 cm⁻¹

5)(2RS,3RS)-2-[4-(difluoromethyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionicacid

To a solution of ethyl(2RS,3RS)-2-[4-(difluoromethyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionate(2.739 g, 7.774 mmol) in methanol (20 ml) and tetrahydrofuran (20 ml)was added 1N aqueous sodium hydroxide solution (15.5 ml, 15.5 mmol) andthe mixture was stirred overnight at room temperature. The reactionsolution was concentrated, diluted with water, acidified with 1Nhydrochloric acid and extracted twice with ethyl acetate. The collectedorganic layer was dried over anhydrous sodium sulfate and the solventwas evaporated under reduced pressure. The residue was crystallized fromhexane to give the objective substance.

white crystal yield 2.232 g, 89% mp 132-133° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.95-3.10 (3H, m), 5.06 (1H, s), 6.60 (1H, t, J=56.6 Hz), 7.05 (2H, t,J 8.8 Hz), 7.16 (2H, d, J=8.0 Hz), 7.33-7.40 (4H, m); IR (KBr) 3349,3020-2550, 1694, 1514, 1238, 1022, 841 cm⁻¹; Anal. Calcd for C₁₇H₁₅F₃O₃:C, 62.96; H, 4.66. Found: C, 63.04; H, 4.85.

6)(4RS,5SR)-4-[4-(difluoromethyl)benzyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-2-[4-(difluoromethyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionicacid (2.060 g, 6.352 mmol) in-tetrahydrofuran (40 ml) were addedtriethylamine (1.33 ml, 9.53 mmol) and diphenylphosphoryl azide (1.92 g,6.99 mmol) and the mixture was heated under reflux overnight. Thesolvent of the reaction solution was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1) and crystallized fromdiethyl ether-hexane to give the objective substance.

white crystal yield 1.888 g, 93% mp 161-162° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.22-2.38 (2H, m), 4.25 (1H, dt, J=4.8 Hz, 8.7 Hz), 5.02 (1H, br s),5.80 (1H, d, J=8.0 Hz), 6.61, (1H, t, J=56.4 Hz), 7.09-7.19 (4H, m),7.34 (2H, dd, J=5.2 Hz, 8.6 Hz), 7.44 (2H, d, J=8.0 Hz); IR (KBr) 3250,1734, 1516, 1383, 1229, 1076, 1032, 849 cm⁻¹; Anal. Calcd forC₁₇H₁₄F₃NO₂: C, 63.55; H, 4.39; N, 4.36. Found: C, 63.63; H, 4.42; N,4.16.

7)(1RS,2SR)-2-amino-3-[4-(difluoromethyl)phenyl]-1-(4-fluorophenyl)propan-1-ol

(4RS,5SR)-4-[4-(Difluoromethyl)benzyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one(1.705 g, 5.307 mmol) and sodium hydroxide (0.85 g, 21.2 mmol) wereheated under reflux in ethanol (20 ml) and water (1 ml) for 6 hrs. Thereaction solution was diluted with water and extracted twice with ethylacetate. The collected organic layer was dried over anhydrous sodiumsulfate and the solvent was evaporated under reduced pressure. Theresidue was crystallized from diisopropyl ether-hexane to give theobjective substance.

white crystal yield 1.268 g, 81% mp 89-90° C.; ¹H-NMR (CDCl₃, 200 MHz) δ2.40 (1H, dd, J=10.3 Hz, 13.1 Hz), 2.84 (1H, d, J=14.0 Hz), 3.24-3.34(1H, m), 4.67 (1H, d, J=4.8 Hz), 6.621 (1H, t, J=56.6 Hz), 7.08 (2H, t,J=8.8 Hz), 7.24 (2H, d, J=8.0 Hz), 7.38 (2H, dd, J=5.6 Hz, 8.6 Hz), 7.44(2H, d, J=8.0 Hz); IR (KBr) 3350 2870, 1593, 1508, 1381, 1215, 1047,1001, 829 cm⁻¹; Anal. Calcd for C₁₆H₁₆F₃NO: C, 65.08; H, 5.46; N, 4.74.Found: C, 65.10; H, 5.72; N, 4.47.

8)N-[(1RS,2SR)-1-[4-(difluoromethyl)benzyl]-2-(4-fluorophenyl)-2-hydroxyethyl]-4-fluoronaphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-3-[4-(difluoromethyl)phenyl]-1-(4-fluorophenyl)propan-1-ol(0.167 g, 0.566 mmol), 4-fluoro-1-naphthoate (0.11 g, 0.57,mmol) and1-hydroxybenzotriazole hydrate (87 mg, 0.57 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11g, 0.57 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from ethyl acetate-diisopropyl ether-hexane to give theobjective substance.

white crystal yield 0.222 g, 84% mp 212-213° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.84-3.05 (2H, m), 4.71-4.85 (1H, m), 4.97-5.16 (2H, m), 6.63(1H, t, J=56.4 Hz), 6.98-7.63 (14H, m), 8.06 (1H, d, J=8.4 Hz); IR (KBr)3274, 1642, 1626, 1537, 1512, 1229, 1030, 837 cm⁻¹; Anal. Calcd forC₂₇H₂₁F₄NO₂: C, 69.37; H, 4.53; N, 3.00. Found: C, 69.11; H, 4.72; N,2.74.

Example 166N-[(1RS,2SR)-1-[4-(1,1-difluoroethyl)benzyl]-2-(4-fluorophenyl)-2-hydroxyethyl]-4-fluoronaphthalene-1-carboxamide

1) methyl 4-(1,1-difluoroethyl)benzoate

To a solution of (diethylamino)sulfur trifluoride (10.6 g, 66.1 mmol) intoluene (30 ml) was added a solution of methyl 4-acetylbenzoate (10.58g, 55.04 mmol) in toluene (50 ml) at −78° C. and the mixture was stirredat room temperature for 1 week and at 50° C. for 1 day. To the reactionsolution was further added (diethylamino)sulfur trifluoride (5.32 g,33.0 mmol) and the mixture was stirred at 60° C. for 3 days. Aqueoussodium hydrogen carbonate solution was added to the reaction solution.The mixture was stirred and the toluene layer was separated. The aqueouslayer was extracted with ethyl acetate. The collected organic layer wasdried over anhydrous magnesium sulfate and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=9/1) to give the objectivesubstance.

yellow liquid yield 3.958 g, 34% ¹H-NMR (CDCl₃, 200 MHz) δ 1.41 (3H, t,J=7.1 Hz), 1.93 (3H, t, J=18.1 Hz), 4.40 (2H, q, J=7.2 Hz), 7.57 (2H, d,J=8.0 Hz), 8.10 (2H, d, J=8.0 Hz); IR (neat) 1721, 1277, 1101 cm⁻¹

2) 4-(1,1-difluoroethyl)benzyl alcohol

To a suspension of lithium aluminum hydride (1.03 g, 27.3 mol) intetrahydrofuran (30 ml) was dropwise added a solution of methyl4-(1,1-difluoroethyl)benzoate (3.894 g, 18.18 mmol) in tetrahydrofuran(50 ml) under ice-cooling and the mixture was stirred at roomtemperature for 1 hr. The reaction solution was ice-cooled and water (1ml), 15% aqueous sodium hydroxide solution (1 ml) and water (2.5 ml)were dropwise added successively to decomposed excess lithium aluminumhydride. The mixture was stirred as it was at room temperature for 2hrs. The resulting precipitate was removed by filtration and theprecipitate was washed with ethyl acetate. The solvent of the collectedfiltrate was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (hexane/ethylacetate=3/1-1/1) to give the objective substance.

colorless liquid yield 2.700 g, 86% ¹H-NMR (CDCl₃, 200 MHz) δ 1.72 (1H,t, J=5.8 Hz), 1.92 (3H, t, J=18.1 Hz), 4.74 (2H, d, J=6.0 Hz), 7.42 (2H,d, J=8.4 Hz), 7.51 (2H, d, J=8.4 Hz); IR (neat) 3330, 1296, 1175, 918cm⁻¹

3) ethyl2-[4-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-oxopropionate

To a solution of 4-(1,1-difluoroethyl)benzyl alcohol (2.65 g, 15.4 mmol)and triethylamine (3.22 ml, 23.1 mmol) in ethyl acetate (40 ml) wasdropwise added a solution of methanesulfonyl chloride (1.94 g, 16.9mmol) in ethyl acetate (10 ml) under ice-cooling and the mixture wasstirred as it was for 10 min. The resulting precipitate was removed byfiltration and the precipitate was washed with ethyl ether. The solventof the collected filtrate was evaporated under reduced pressure to givea crude product of the methanesulfonic acid ester as a yellow liquid.

To a solution of ethyl (4-fluorobenzoyl)acetate (3.235 g, 15.39 mmol) in1,2-dimethoxyethane (30 ml) was added a suspension (0.62 g, 15.4 mmol)of 60% sodium hydride in liquid paraffin under ice-cooling and themixture was stirred as it was for 0.5 hr. A solution of themethanesulfonic acid ester obtained above in 1,2-dimethoxyethane (10 ml)was added thereto at room temperature and the mixture was stirred atroom temperature for 8 hrs. The reaction solution was poured into waterand extracted twice with ethyl acetate. The collected organic layer wasdried over anhydrous magnesium sulfate and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=15/1-9/1) and crystallizedfrom hexane to give the objective substance.

white crystal yield 2.790 g, 50% mp 56-57° C.; ¹H-NMR (CDCl₃, 200 MHz) δ1.12 (3H, t, J=7.2 Hz), 1.88 (3H, t, J=18.2 Hz), 3.35 (2H, d, J=7.2 Hz),4.11 (2H, q, J=7.2 Hz), 4.57 (1H, t, J=7.4 Hz), 7.13 (2H, t, J=8.6 Hz),7.28 (2H, d, J=8.0 Hz), 7.40 (2H, d, J=8.0 Hz), 8.00 (2H, dd, J=5.4 Hz,8.8 Hz); IR (KBr) 1719, 1678, 1599, 1300, 1231, 1154, 924, 847 cm⁻¹;Anal. Calcd for C₂₀H₁₉F₃O₃: C, 65.93; H, 5.26. Found: C, 66.03; H, 5.28.

4) ethyl(2RS,3RS)-2-[4-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionate

While stirring zinc chloride (1.91 g, 14.0 mmol) in diethyl ether (50ml), sodium borohydride (1.06 g, 28.1 mmol) was added at roomtemperature and the mixture was stirred as it was for 2 hrs. Theinsoluble material of the mixture was removed by filtration and washedwith diethyl ether to give a solution of zinc borohydride in diethylether. To the obtained solution was added a solution of ethyl2-[4-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-oxopropionate(2.556 g, 7.015 mmol) in diethyl ether (30 ml) at room temperature andthe mixture was stirred as it was for 2 hrs. To the reaction solutionwas added dilute hydrochloric acid by small portions to decompose excesszinc borohydride and the mixture was extracted twice with ethyl acetate.The collected organic layer was dried over anhydrous magnesium sulfateand the solvent was evaporated under reduced pressure. The obtainedcrude product was purified by silica gel column chromatography(hexane/ethyl acetate=6/1−3/1) to give the objective substance.

colorless liquid yield 2.615 g, 100% ¹H-NMR (CDCl₃, 200 MHz) δ 0.92 (3H,t, J=7.1 Hz), 1.88 (3H, t, J=18.2 Hz), 2.91 (1H, d, J=2.6 Hz), 2.94-3.12(3H, m), 3.88 (2H, q, J=7.2 Hz), 5.02 (1H, t, J=3.6 Hz), 7.05 (2H, t,J=8.6 Hz), 7.14 (2H, d, J=8.2 Hz), 7.35-7.41 (4H, m); IR (neat) 3461,1717, 1510, 1298, 1225, 1177, 1159, 837 cm⁻¹

5)(2RS,3RS)-2-[4-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionicacid

To a solution of ethyl(2RS,3RS)-2-[4-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionate(2.489 g, 6.793 mmol) in methanol (20 ml) and tetrahydrofuran (20 ml)was added 1N aqueous sodium hydroxide solution (13.6 ml, 13.6 mmol) andthe mixture was stirred overnight at room temperature. The reactionsolution was concentrated, diluted with water, acidified with 1Nhydrochloric acid and extracted twice with ethyl acetate. The collectedorganic layer was dried over anhydrous sodium sulfate and the solventwas evaporated under reduced pressure. The residue was crystallized fromhexane to give the objective substance.

white crystal yield 1.986 g, 86% mp 127-128° C.; ¹H-NMR (CDCl₃, 200MHz.) δ 1.89 (3H, t, J=18.1 Hz), 2.89-3.10 (3H, m), 5.06 (1H, d, J=3.2Hz), 7.05 (2H, t, J=8.7 Hz), 7.13 (2H, d, J=8.4 Hz), 7.33-7.39 (4H, m);IR (KBr) 3330, 3010-2550, 1688, 1518, 1300, 1240, 1225, 1198, 839 cm⁻¹;Anal. Calcd for C₁₈H₁₇F₃O₃: C, 63.90; H, 5.06. Found: C, 64.09; H, 5.03.

6)(4RS,5SR)-4-[4-(1,1-difluoroethyl)benzyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one

To a-solution of(2RS,3RS)-2-[4-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionicacid (1.836 g, 5.427 mmol) in tetrahydrofuran (40 ml) were addedtriethylamine (1.13 ml, 8.14 mmol) and diphenylphosphoryl azide (1.64 g,5.97 mmol) and the mixture was heated under reflux overnight. Thesolvent of the reaction solution was evaporated under reduced pressure,the obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1) and crystallized fromdiethyl ether-hexane to give the objective substance.

white crystal yield 1.704 g, 94% mp 205-206° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.90 (3H, t, J=18.2 Hz), 2.19-2.40 (2H, m), 4.23 (1H, dt, J=5.3 Hz,8.7 Hz), 4.92 (1H, br s), 5.80 (1H, d, J=8.0 Hz), 7.09 (2H, d, J=7.6Hz), 7.14 (2H, t, J=8.8 Hz), 7.37 (2H, dd, J=5.0 Hz, 8.4 Hz), 7.43 (2H,d, J=8.8 Hz); IR (KBr) 3245, 1732, 1385, 1300, 1231, 1107, 1011, 924cm⁻¹; Anal. Calcd for C₁₈H₁₆F₃NO₂: C, 64.47; H, 4.81; N, 4.18. Found: C,64.47; H, 4.82; N, 4.02.

7)(1RS,2SR)-2-amino-3-[4-(1,1-difluoroethyl)phenyl]-1-(4-fluorophenyl)propan-1-ol

(4RS,5SR)-4-[4-(1,1-Difluoroethyl)benzyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one(1.557 g, 4.643 mmol) and sodium hydroxide (0.74 g, 18.6 mmol) wereheated under reflux in ethanol (20 ml) and water (1 ml) for 6 hrs. Thereaction solution was diluted with water and extracted twice with ethylacetate. The collected organic layer was dried over anhydrous sodiumsulfate and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel (APS type) column chromatography(hexane/ethyl acetate=3/1-ethyl acetate) to give the objectivesubstance.

yellow liquid yield 0.916 g, 64% ¹H-NMR (CDCl₃, 200 MHz) δ 1.91 (3H, t,J=18.3 Hz), 2.38 (1H, dd, J=10.4 Hz, 13.6 Hz), 2.83 (1H, dd, J=3.0 Hz,13.8 Hz), 3.29 (1H, ddd, J=3.3 Hz, 4.8 Hz, 10.3 Hz), 4.67 (1H, d, J=5.2Hz), 7.08 (2H, t, J=8.8 Hz), 7.20 (2H, d, J=7.6 Hz), 7.38 (2H, dd, J=5.6Hz, 8.4 Hz), 7.44 (2H, d, J=7.6 Hz); IR (neat) 3360-2860, 1605, 1508,2385, 1298, 1223, 1175, 918, 826 cm⁻¹

8)N-[(1RS,2SR)-1-[4-(1,1-difluoroethyl)benzyl]-2-(4-fluorophenyl)-2-hydroxyethyl]-4-fluoronaphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-3-[4-(1,1-difluoroethyl)phenyl]-1-(4-fluorophenyl)propan-1-ol(0.173 g, 0.559 mmol), 4-fluoro-1-naphthoate (0.11 g, 0.56 mmol) and1-hydroxybenzotriazole hydrate (86 mg, 0.56 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11g, 0.56 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from ethyl acetate-diisopropyl ether to give the objectivesubstance.

white crystal yield 0.245 g, 91% mp 220-221° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 1.90 (3H, t, J=18.1 Hz), 2.84-3.06 (2H, m), 4.69-4.84 (1H,m)), 5.03 (1H, t, J=3.5 Hz), 5.16 (1H, d, J=3.8 Hz), 6.99-7.12 (3H, m),7.18-7.30 (4H, m), 7.39-7.65 (7H, m), 8.06 (1H, d, J=8.4 Hz); IR (KBr)3281, 1642, 1626, 1539, 1512, 1298, 1231, 1163, 843, 835, 758 cm⁻¹;Anal. Calcd for C₂₈H₂₃F₄NO₂: C, 69.85; H, 4.81; N, 2.91. Found: C,69.70; H, 4.98; N, 2.84.

Example 167N-[(1RS,2SR)-1-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-2-(4-fluorophenyl)-2-hydroxyethyl]-4-fluoronaphthalene-1-carboxamide

1) (2,2-difluoro-1,3-benzodioxol-5-yl)methanol

To a suspension of lithium aluminum hydride (1.86 g, 48.9 mmol) intetrahydrofuran (30 ml) was dropwise added a solution of2,2-difluoro-1,3-benzodioxole-5-carboxylic acid (4.942 g, 24.45 mmol) intetrahydrofuran (30 ml) under ice-cooling and the mixture was stirred atroom temperature for 1 hr. The reaction solution was ice-cooled andwater (2 ml), 15% aqueous sodium hydroxide solution (2 ml) and water (5ml) was dropwise added successively to decompose excess lithium aluminumhydride. The mixture was stirred as it was at room temperature for 2hrs. The resulting-precipitate was removed by filtration and theprecipitate was washed with ethyl acetate. The solvent of the collectedfiltrate was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (hexane/ethylacetate=6/1−1/1) to give the objective substance.

colorless liquid yield 3.658 g, 80% ¹H-NMR (CDCl₃, 200 MHz) δ 1.73 (1H,t, J=6.0 Hz), 4.68 (2H, d, J=5.8 Hz), 7.02 (1H, d, J=8.4 Hz), 7.08 (1H,d, J=8.0 Hz), 7.23 (1H, s); IR (neat) 3318, 1501, 1449, 1238, 1148, 1036cm⁻¹

2) ethyl2-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-3-(4-fluorophenyl)-3-oxopropionate

To a solution of (2,2-difluoro-1,3-benzodioxol-5-yl)methanol (3.60 g,19.1 mmol) and triethylamine (4.00 ml, 28.7 mmol) in ethyl acetate (40ml) was dropwise added a solution of methanesulfonyl chloride (2.41 g,21.1 mmol) in ethyl acetate (10 ml) under ice-cooling and the mixturewas stirred as it was for 10 min. The resulting precipitate was removedby filtration and the precipitate was washed with diethyl ether. Thesolvent of the collected filtrate was evaporated under reduced pressureto give a crude product of the methanesulfonic acid ester as a yellowliquid.

To a solution of ethyl (4-fluorobenzoyl)acetate (4.024 g, 19.14 mmol) in1,2-dimethoxyethane (30 ml) was added a suspension (0.77 g, 19.1 mmol)of 60% sodium hydride in liquid paraffin under ice-cooling and themixture was stirred as it was for 0.5 hr. A solution of themethanesulfonic acid ester obtained above in 1,2-dimethoxyethane (10 ml)was added thereto at room temperature and the mixture was stirred atroom temperature for 8 hrs. The reaction solution was poured into waterand extracted twice with ethyl acetate. The collected organic layer wasdried over anhydrous magnesium sulfate and the solvent was evaporatedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=15/1-9/1) and crystallizedfrom hexane to give the objective substance.

white crystal yield 5.047 g, 69% mp 66-67° C.; ¹H-NMR (CDCl₃, 200 MHz) δ1.13 (3H, t, J=7.2 Hz), 3.31 (2H, d, J=7.4 Hz), 4.11 (2H, q, J=7.2 Hz),4.51 (1H, t, J=7.3 Hz), 6.93-6.97 (3H, m), 7.14 (2H, t, J=8.6 Hz), 8.00(2H, dd, J=5.4 Hz, 9.0 Hz); IR (KBr) 1725, 1682, 1597, 1501, 1258, 1233,1150 cm⁻¹; Anal. Calcd for C₁₉H₁₅F₃O₅: C, 60.00; H, 3.98. Found: C,60.03; H, 4.02.

3) ethyl(2RS,3RS)-2-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-3-(4-fluorophenyl)-3-hydroxypropionate

While stirring zinc chloride (3.50 g, 25.7 mmol) in diethyl ether (50ml), sodium borohydride (1.94 g, 51.4 mmol) was added at roomtemperature and the mixture was stirred as it was for 2 hrs. Theinsoluble material of the mixture was removed by filtration and washedwith diethyl ether to give a solution of zinc borohydride in diethylether. To the obtained solution was added a solution of ethyl2-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-3-(4-fluorophenyl)-3-oxopropionate(4.888 g, 12.85 mmol) in diethyl ether (30 ml) at room, temperature andthe mixture was stirred as it was for 2 hrs. To the reaction solutionwas added dilute hydrochloric acid by small portions to decompose excesszinc borohydride and the mixture was extracted twice with ethyl acetate.The collected organic layer was dried over anhydrous magnesium sulfateand the solvent was evaporated-under reduced pressure. The obtainedcrude product was purified by silica gel column chromatography(hexane/ethyl acetate=6/1−3/1) to give the objective substance.

colorless liquid yield 4.849 g, 99% ¹H-NMR (CDCl₃, 200 MHz) δ 0.96 (3H,t, J=7.1 Hz), 2.82 (1H, d, J=2.6 Hz), 2.85-3.02 (3H, m), 3.91 (2H, q,J=7.1 Hz), 4.99 (1H, dd, J=2.5 Hz, 5.1 Hz), 6.75-6.81 (2H, m), 6.91 (1H,d, J=8.0 Hz), 7.05 (2H, t, J=8.6 Hz), 7.36 (2H, dd, J=5.3 Hz, 8.7 Hz);IR (neat) 3468, 1725, 1499, 1449, 1240, 1155, 1036, 839 cm⁻¹

4)(2RS,3RS)-2-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-3-(4-fluorophenyl)-3-hydroxypropionicacid

To a solution of ethyl(2RS,3RS)-2-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-3-(4-fluorophenyl)-3-hydroxypropionate(4.725 g, 12.36 mmol) in methanol (30 ml) and tetrahydrofuran (30 ml)was added 1N aqueous sodium hydroxide solution (24.7 ml, 24.7 mmol) andthe mixture was stirred overnight at room temperature. The reactionsolution was concentrated, diluted with water, acidified with 1Nhydrochloric acid and extracted twice with ethyl acetate. The collectedorganic layer was dried over anhydrous sodium sulfate and the solventwas evaporated under reduced pressure. The residue was crystallized fromhexane to give the objective substance.

white crystal yield 3.743 g, 86% mp 115-117° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.97 (3H, s), 5.03-5.06 (1H, m), 6.76 (1H, dd, J=1.6 Hz, 8.2 Hz), 6.80(1H, s), 6.90 (1H, d, J=8.2 Hz), 7.05 (2H, t, J=8.6 Hz), 7.36 (2H, dd,J=5.4 Hz, 8.6 Hz); IR (KBr) 3333, 3100-2550, 1694, 1518, 1499, 1447,1273, 1260, 1244, 1163, 1148, 841 cm⁻¹; Anal. Calcd for C₁₇H₁₃F₃O₅: C,57.63; H, 3.70. Found: C, 57.64; H, 3.51.

5)(4RS,5SR)-4-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-2-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-3-(4-fluorophenyl)-3-hydroxypropionicacid (3.387 g, 9.560 mmol) in tetrahydrofuran (50 ml) were addedtriethylamine (2.00 ml, 14.3 mmol) and diphenylphosphoryl azide (2.89 g,10.5 mmol) and the mixture was heated under reflux overnight. Thesolvent of the reaction solution was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1) and crystallized fromdiethyl ether-hexane to give the objective substance.

white crystal yield 3.144 g, 94% mp 177-178° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.16-2.35 (2H, m), 4.13-4.25 (1H, m), 5.10 (1H, br s), 5.79 (1H, d,J=7.6 Hz), 6.72 (1H, d, J=8.4 Hz), 6.74 (1H, s), 6.98 (1H, d, J=8.6 Hz),7.14 (2H, t, J=8.6 Hz), 7.36 (2H, dd, J=5.0 Hz, 8.8 Hz); IR (KBr) 3241,3139, 1736, 1501, 1258, 1238, 1152 cm⁻¹; Anal. Calcd for C₁₇H₁₂F₃NO₄: C,58.13; H, 3.44; N, 3.99. Found: C, 58.16; H, 3.42; N, 3.85.

6)(1RS,2SR)-2-amino-3-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-(4-fluorophenyl)propan-1-ol

(4RS,5SR)-4-[(2,2-Difluoro-1,3-benzodioxol-5-yl)methyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one(2.962 g, 8.432 mmol) and sodium hydroxide (1.35 g, 33.7 mmol) wereheated under reflux in ethanol (30 ml) and water (1.5 ml) for 6 hrs. Thereaction solution was diluted with water and extracted twice with ethylacetate. The collected organic layer was dried over anhydrous sodiumsulfate and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel (APS type) column chromatography(hexane/ethyl acetate=3/1-ethyl acetate) and crystallized fromdiisopropyl ether-hexane to give the objective substance.

white crystal yield 2.225 g, 81% mp. 77-78° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.36 (1H, dd, J=10.1 Hz, 13.7 Hz), 2.81 (1H, dd, J=3.1 Hz, 13.7 Hz),3.22 (1H, ddd, J=3.2 Hz, 5.2 Hz, 10.0 Hz), 4.63 (1H, d, J=5.2 Hz),6.82-6.87 (2H, m), 6.97 (1H, d, J=8.0 Hz), 7.08 (2H, t, J=8.8 Hz), 7.37(2H, dd, J=5.4 Hz, 8.6 Hz); IR (KBr) 3340-2865, 1501, 1447, 1262, 1242,1213, 1157, 1063, 779 cm⁻¹; Anal. Calcd for C₁₆H₁₄F₃NO₃: C, 59.08; H,4.34; N, 4.31. Found: C, 59.08; H, 4.39; N, 4.10.

7)N-[(1RS,2SR)-1-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-2-(4-fluorophenyl)-2-hydroxyethyl]-4-fluoronaphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-3-(2,2-difluoro-1,3-benzodioxol-5-yl)-1-(4-fluorophenyl)propan-1-ol(0.167 g, 0.513 mmol), 4-fluoro-1-naphthoate (0.10 g, 0.51 mmol) and1-hydroxybenzotriazole hydrate (79 mg, 0.51 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10g, 0.51 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white crystal yield 0.230 g, 90% mp 219-220° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.85 (1H, dd, J=10.0 Hz, 14.4 Hz), 2.97 (1H, dd, J=4.2 Hz,13.8 Hz), 4.64-4.78 (1H, m), 5.01 (1H, t, J=3.8 Hz), 5.10 (1H, d, J=3.6Hz), 6.93-7.13 (6H, m), 7.25-7.58 (6H, m), 7.69 (1H, d, J=8.0 Hz), 8.07(1H, d, J=8.0 Hz); IR (KBr) 3266, 1644, 1626, 1541, 1514, 1497, 1244,1146 cm⁻¹; Anal. Calcd for C₂₇H₁₉F₄NO₄: C, 65.19; H, 3.85; N, 2.82.Found: C, 65.22; H, 3.87; N, 2.57.

Example 168 tert-butylN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl]ethyl]carbamate

1) ethyl 2-(trifluoromethyl)-1,3-thiazole-5-carboxylate

2,2,2-Trifluoroacetamide (12.27 g, purity 85%, 80.8 mmol), potassiumsalt of ethyl chloroformylacetate (15.2 g, 80.8 mmol) and acetic acid(4.85 g, 80.8 mmol) were heated under reflux in ethanol (100 ml)overnight. The solvent of the reaction solution was evaporated underreduced pressure. The residue was diluted with aqueous sodium-hydrogencarbonate solution and extracted twice with ethyl acetate. The collectedorganic layer was dried over anhydrous sodium sulfate and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=9/1) to give theobjective substance.

yellow liquid yield 12.72 g, 70% ¹H-NMR (CDCl₃, 200 MHz) δ 1.41 (3H, t,J=7.1 Hz), 4.43 (2H, q, J=7.1 Hz), 8.49 (1H, s); IR (neat) 1728, 1522,1304, 1285, 1246, 1196, 1152, 1094, 1038 cm⁻¹

2) [2-(trifluoromethyl)-1,3-thiazol-5-yl]methanol

To a suspension of lithium aluminum hydride (2.17 g, 57.1 mmol) intetrahydrofuran (80 ml) was dropwise added a solution of ethyl2-(trifluoromethyl)-1,3-thiazole-5-carboxylate (8.579 g, 38.10 mmol) intetrahydrofuran (40 ml) under ice-cooling and the mixture was stirred at0° C. 1 hr. The reaction solution was ice-cooled and water (2 ml), 15%aqueous sodium hydroxide solution (2 ml) and water (5 ml) were dropwiseadded successively to decompose excess lithium aluminum hydride. Themixture was stirred at room temperature as it was for 2 hrs. Theresulting precipitate was removed by filtration and the precipitate waswashed with ethyl acetate. The solvent of the collected filtrate wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (hexane/ethyl acetate=6/1−1/1) to givethe objective substance.

brown liquid yield 5.499 g, 79% ¹H-NMR (CDCl₃, 200 MHz) δ 2.24 (1H, t,J=5.7 Hz), 4.97 (2H, d, J=5.6 Hz), 7.82 (1H, s); IR (neat) 3308, 1532,1456, 1333, 1312, 1196, 1144, 1036 cm⁻¹

3) ethyl3-(4-fluorophenyl)-3-oxo-2-[[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl]propionate

To a solution of [2-(trifluoromethyl)-1,3-thiazol-5-yl]methanol (2.61 g,14.3 mmol) and triethylamine (2.39 ml, 17.1 mmol) in ethyl acetate (40ml) was dropwise added a solution of methanesulfonyl chloride (1.80 g,15.7 mmol) in ethyl acetate (10 ml) under ice-cooling and the mixturewas stirred as it was for 10 min. The resulting precipitate was removedby filtration and the precipitate was washed with diethyl ether. Thesolvent of the collected filtrate was evaporated under reduced pressureto give a crude product of methanesulfonic acid ester as a yellowliquid.

To a solution of ethyl (4-fluorobenzoyl)acetate (2.998 g, 14.26 mmol) in1,2-dimethoxyethane (30 ml) was added a suspension (0.57 g, 14.3 mmol)of 60% sodium hydride in liquid paraffin under ice-cooling and themixture was stirred as it was for 0.5 hr. A solution of themethanesulfonic acid ester obtained above in 1,2-dimethoxyethane (10 ml)was added thereto at room temperature and the mixture was stirredovernight at room temperature. The reaction solution was poured intowater and extracted twice with ethyl acetate. The collected organiclayer was dried over anhydrous magnesium sulfate and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (hexane/ethyl acetate=9/1-6/1) to givethe objective substance.

white crystal yield 4.275 g, 80% ¹H-NMR (CDCl₃, 200 MHz) δ 1.15 (3H, t,J=7.1 Hz), 3.61 (2H, d, J=7.0 Hz), 4.15 (2H, q, J=7.1 Hz), 4.57 (1H, t,J=7.1 Hz), 7.17 (2H, t, J=8.6 Hz), 7.70 (1H, s), 8.04 (2H, dd, J=5.3 Hz,8.9 Hz); IR (neat) 1740, 1732, 1682, 1599, 1508, 1456, 1329, 1300, 1238,1194, 1157, 1034, 849 cm⁻¹

4) ethyl(1RS,2RS)-3-(4-fluorophenyl)-3-hydroxy-2-[[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl]propionate

While stirring zinc chloride (2.80 g, 20.5 mmol) in diethyl ether (50ml), sodium borohydride (1.55 g, 41.1 mmol) was added at roomtemperature and the mixture was stirred as it was for 2 hrs. Theinsoluble material of the mixture was removed by filtration and washedwith diethyl ether to give a solution of zinc borohydride in diethylether. To the obtained solution was added a solution of ethyl3-(4-fluorophenyl)-3-oxo-2-[[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl]propionate(3.856 g, 10.27 mmol) in diethyl ether (30 ml) at room temperature andthe mixture was stirred as it was for 2 hrs. To the reaction solutionwas added dilute hydrochloric acid by small portions to decompose excesszinc borohydride and the mixture was extracted twice with ethyl acetate.The collected organic layer was dried over anhydrous magnesium sulfateand the solvent was evaporated under reduced pressure. The obtainedcrude product was purified by silica gel column chromatography(hexane/ethyl acetate=6/1−3/1) to give the objective substance.

colorless liquid yield 1.989 g, 51% ¹H-NMR (CDCl₃, 200 MHz) δ 1.27 (3H,t, J=7.1 Hz), 2.64 (1H, d, J=3.0 Hz), 2.98 (1H, ddd, J=4.0 Hz, 6.2 Hz,10.2 Hz), 3.23 (1H, dd, J=4.2 Hz, 15.2 Hz), 3.39 (1H, dd, J=10.2 Hz,15.2 Hz), 3.99 (2H, q, J=7.1 Hz), 5.03 (1H, dd, J=2.9 Hz, 6.3 Hz), 7.06(2H, t, J=8.6 Hz), 7.36 (2H, dd, J=5.3 Hz, 8.7 Hz), 7.59 (1H, s); IR(neat) 3409, 1726, 1510, 1454, 1329, 1300, 1225, 1192, 1150, 1034, 839cm⁻¹

5)(1RS,2RS)-3-(4-fluorophenyl)-3-hydroxy-2-[[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl]propionicacid

To a solution of ethyl(1RS,2RS)-3-(4-fluorophenyl)-3-hydroxy-2-[[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl]propionate(1.883 g, 4.990 mmol) in methanol (20 ml) was added 1N aqueous sodiumhydroxide solution (9.98 ml, 9.98 mmol) and the mixture was stirredovernight at room temperature. The reaction solution was concentrated,diluted with water, acidified with 1N hydrochloric acid and extractedtwice with ethyl acetate. The collected organic layer was dried overanhydrous sodium sulfate and the solvent was evaporated under reducedpressure. The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1) to give the objectivesubstance.

pale-yellow liquid yield 1.420 g, 82% ¹H-NMR (CDCl₃, 200 MHz) δ 3.04(1H, ddd, J=4.0 Hz, 5.8 Hz, 9.7 Hz), 3.18 (1H, dd, J=3.6 Hz, 15.0 Hz),3.40 (1H, dd, J=10.0 Hz, 15.4 Hz), 5.13 (1H, d, J=5.4 Hz), 7.08 (2H, t,J=8.8 Hz), 7.38 (2H, dd, J=5.4 Hz, 8.6 Hz), 7.59 (1H, s); IR (neat)3500-2900, 1715, 1510, 1456, 1331, 1300, 1227, 1196, 1152, 1040, 841cm⁻¹

6)(4RS,5SR)-5-(4-fluorophenyl)-4-[[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl]-1,3-oxazolidin-2-one

To a solution of(1RS,2RS)-3-(4-fluorophenyl)-3-hydroxy-2-[[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl]propionicacid (1.310 g, 1.310 mmol) in tetrahydrofuran (50 ml) were addedtriethylamine (0.78 ml, 5.63 mmol) and diphenylphosphoryl azide (1.14 g,4.13 mmol) and the mixture was heated under reflux overnight. Thesolvent of the reaction solution was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1) to give the objectivesubstance.

¹H-NMR (CDCl₃, 200 MHz) δ 2.58 (1H, dd, J=5.2 Hz, 15.0 Hz) 2.69 (1H, dd,J=8.8 Hz, 15.0 Hz), 4.23-4.35 (1H, m), 5.67 (1H, br s), 5.83 (1H, d,J=7.6 Hz), 7.13 (2H, t, J=8.6 Hz), 7.32 (2H, dd, J=5.2 Hz, 8.8 Hz), 7.49(1H, s); IR (neat) 3272, 1780-1730, 1514, 1456, 1331, 1300, 1233, 1194,1148, 1032 cm⁻¹

7) tert-butyl(4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-[[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl]-1,3-oxazolidine-3-carboxylate

A solution of(4RS,5SR)-5-(4-fluorophenyl)-4-[[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl]-1,3-oxazolidin-2-one(1.062 g, 3.067 mmol), di-tert-butyl dicarbonate (0.80 g, 3.68 mmol) and4-N,N-dimethylaminopyridine (37 mg, 0.31 mmol) in acetonitrile (10 ml)was stirred overnight at room temperature. The reaction solution wasdiluted with ethyl acetate, washed with water, dried over anhydrousmagnesium sulfate and passed through silica gel. The solvent wasevaporated under reduced pressure. The obtained residue was crystallizedfrom ethyl acetate-hexane to give the objective substance.

white crystal yield 1.186 g, 87% mp 192-193° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.55 (9H, s), 2.99 (1H, dd, J=7.4 Hz, 15.0 Hz), 3.09 (1H, dd, J=5.2Hz, 15.4 Hz), 4.75 (1H, dt, J=4.9 Hz, 14.9 Hz), 5.73 (1H, d, J=7.0 Hz),7.04 (1H, s), 7.06 (2H, t, J=8.6 Hz), 7.22 (2H, dd, J=5.2 Hz, 8.4 Hz);IR (KBr) 1792, 1370, 1304, 1192, 1163, 1034 cm⁻¹; Anal. Calcd forC₁₉H₁₈F₄N₂O₄S: C, 51.12; H, 4.06; N, 6.28. Found: C, 50.94; H, 4.10; N,6.48.

8) tert-butylN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl]ethyl]carbamate

To a solution of tert-butyl(4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-[[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl]-1,3-oxazolidine-3-carboxylate(1.079 g, 2.417 mmol) in methanol (10 ml) and tetrahydrofuran (10 ml)was added a solution of sodium hydroxide (0.11 g, 2.66 mmol) in methanol(5 ml) under ice-cooling and the mixture was stirred at room temperaturefor 3 hrs. The reaction solution was diluted with ethyl acetate, washedwith water, dried over anhydrous magnesium sulfate and passed throughsilica gel. The solvent was evaporated under reduced pressure. Theobtained residue was crystallized from diisopropyl ether-hexane to givethe objective substance.

white crystal yield 0.842 g, 83% mp 137-138° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.38 (9H, s), 2.61 (1H, br s), 3.07 (2H, d, J=7.0 Hz), 3.94-4.05 (1H,m), 4.76 (1H, br d, J=8.4 Hz), 4.91 (1H, br s), 7.08 (2H, t, J=8.6 Hz),7.38 (2H, dd, J=5.4 Hz, 8.6 Hz), 7.61 (1H, s); IR (KBr) 3337, 1682,1532, 1138, 1038 cm⁻¹; Anal. Calcd for C₁₈H₂₀F₄N₂O₃S: C, 51.42; H, 4.79;N, 6.66. Found: C, 51.50; H, 4.70; N, 6.90.

Example 1694-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl]ethyl]naphthalene-1-carboxamide

1)(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[2-(trifluoromethyl)-1,3-thiazol-5-yl]propan-1-ol

A solution of tert-butylN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl]ethyl]carbamate(0.711 g, 1.691 mmol) and conc. hydrochloric acid (0.5 ml) in methanol(5 ml) was heated under reflux for 10 min. The reaction solution wasdiluted with water, alkalified with potassium carbonate and extractedtwice with ethyl acetate. The collected organic layer was dried overanhydrous sodium sulfate and the solvent was evaporated under reducedpressure. The residue was purified by silica gel (APS type) columnchromatography (ethyl acetate) to give the objective substance.

colorless liquid yield 0.534 g, 99% ¹H-NMR (CDCl₃, 200 MHz) δ 2.82 (1H,dd, J=9.4 Hz, 14.8 Hz), 3.08-3.26 (2H, m), 4.56 (1H, d, J=5.8 Hz), 7.09(2H, t, J=8.6 Hz), 7.36 (2H, dd, J=5.6 Hz, 8.8 Hz), 7.68 (1H, s); IR(neat) 3364, 1507, 1456, 1331, 1300, 1225, 1192, 1144, 1032, 837 cm⁻¹

2)4-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[[2-(trifluoromethyl)-1,3-thiazol-5-yl]methyl]ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[2-(trifluoromethyl)-1,3-thiazol-5-yl]propan-1-ol(0.226 g, 0.702 mmol), 4-fluoro-1-naphthoate (0.13 g, 0.71 mmol) and1-hydroxybenzotriazole hydrate (0.11 g, 0.71 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.14g, 0.71 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white crystal yield 0.301 g, 87% mp 197-198° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 3.28 (2H, d, J=7.0 Hz), 4.62-4.76 (1H, m), 4.97 (1H, t, J=3.9Hz), 5.18 (1H, d, J=3.2 Hz), 7.08 (2H, t, J=8.8 Hz), 7.11 (1H, d, J=9.2Hz), 7.38 (1H, dd, J=5.4 Hz, 7.8 Hz), 7.47-7.65 (5H, m), 7.68 (1H, s),7.80-7.86 (1H, m), 8.08-8.12 (1H, m); IR (KBr) 3264, 1642, 1626, 1601,1535, 1512, 1454, 1331, 1300, 1227, 1192, 1140, 1040, 760 cm⁻¹; Anal.Calcd for C₂₄H₁₇F₅N₂O₂S: C, 58.53; H, 3.48; N, 5.69. Found: C, 58.30; H,3.68; N, 5.76.

Example 170N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((3-(2,2,2-trifluoroethoxy)phenyl)methyl)ethyl)-4-fluoro-1-naphthalenecarboxamide

1) To a solution of 3-hydroxytoluene (5.0 g, 46.2 mmol) inN,N-dimethylformamide (50 ml) were added 2,2,2-trifluoro-1-iodoethane(10.7 g, 50.9 mmol) and potassium carbonate (12.8 g, 92.5 mmol) and themixture was stirred overnight at 80° C. The reaction solution wasdiluted with water (200 ml) and extracted with diethyl ether (300 ml×2).The extract was washed successively with water and saturated brine,dried-over anhydrous magnesium sulfate and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=10:1) to give 3-(2,2,2-trifluoroethoxy)toluene(7.60 g, 86%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1752, 1680, 1615, 1588, 1487. ¹H-NMR (CDCl₃)δ: 2.34(3H, s), 4.33 (2H, q, J=8.0 Hz), 6.70-6.90 (3H, m), 7.20 (1H, t, J=7.6Hz).

2) To a solution of 3-(2,2,2-trifluoroethoxy)toluene (7.34 g, 38.6 mmol)in carbon tetrachloride (100 ml) were added N-bromosuccinimide (7.56 g,42.5 mmol) and 2,2′-azobis(isobutyronitrile) (633 mg, 3.86 mmol) and themixture was heated under reflux overnight. The insoluble material wasfiltered using celite and the filtrate was concentrated to prepare abromo form. To a solution of ethyl 3-oxo-3-(4-fluorophenyl)propionate(7.3 g, 34.7 mmol) in 1,2-dimethoxyethane (70 ml) was added sodiumhydride (60% in oil, 1.39 g, 34.7 mmol) under ice-cooling and themixture was stirred at room temperature for 30 min. To the reactionsolution was dropwise added a solution of the bromo form synthesizedabove in 1,2-dimethoxyethane (20 ml) and the reaction solution wasstirred at room temperature for 1 hr. The reaction solution was pouredinto water (200 ml) and extracted with ethyl acetate (200 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=4:1)and recrystallized from diisopropyl ether-hexane to giveethyl-3-(4-fluorophenyl)-3-oxo-2-((3-(2,2,2-trifluoroethoxy)phenyl)methyl)propionate(4.23 g, 31%).

mp 48-49° C. IR ν max^(KBr)cm⁻¹: 1738, 1688, 1599, 1508, 1493, 1453.Anal. Calcd for C₂₀H₁₈F₄O₄: C, 60.30; H, 4.55. Found: C, 60.11; H, 4.36.¹H-NMR (CDCl₃)δ: 1.23 (3H, t, J=7.0 Hz), 3.30 (2H, d, J=7.2 Hz), 4.11(2H, q, J=7.0 Hz), 4.30 (2H, q, J=8.0 Hz), 4.56 (1H, t, J=7.2 Hz),6.70-6.96 (3H, m), 7.06-7.30 (3H, m), 7.92-8.10 (2H, m).

3) To a solution of zinc chloride (2.81 g, 20.6 mmol) in diethyl ether(100 ml) was added sodium borohydride (1.56 g, 41.2 mmol) and themixture was stirred at room temperature for 30 min. The insolublematerial was filtered off. To the filtrate was added a solution of ethyl3-(4-fluorophenyl)-3-oxo-2-((3-(2,2,2-trifluoroethoxy)phenyl)methyl)propionate(4.10 g, 10.3 mmol) in diethyl ether (50 ml) and the mixture was stirredat room temperature for 30 min. 1N Hydrochloric acid was added to thereaction solution under ice-cooling for quenching, water (200 ml) wasadded, and the mixture was extracted with ethyl acetate (300 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=4:1)to give ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(2,2,2-trifluoroethoxy)phenyl)methyl)propionate(3.51 g, 85%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1715, 1605, 1590, 1510. Anal. Calcd forC₂₀H₂₀F₄O₄.0.1H₂O: C, 59.73; H, 5.06. Found: C, 59.55; H, 5.06. ¹H-NMR(CDCl₃)δ: 0.94 (3H, t, J=7.0 Hz), 2.88-3.00 (3H, m), 3.90 (2H, q, J=7.0Hz), 4.30 (2H, q, J=8.0 Hz), 5.01 (1H, brs), 6.60-6.82 (3H, m),7.00-7.30 (3H, m), 7.32-7.44 (2H, m).

4) To a solution of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(2,2,2-trifluoroethoxy)phenyl)methyl)propionate(3.4 g, 8.49 mmol) in methanol (15 ml) was added 2N aqueous sodiumhydroxide solution (8.5 ml, 17.0 mmol) and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid and extracted with ethyl acetate (100 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to give(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(2,2,2-trifluoroethoxy)phenyl)methyl)propionicacid (2.78 g, 88%).

mp 142-143° C. IR ν max^(KBr)cm⁻¹: 1715, 1607, 1588. Anal. Calcd forC₁₈H₁₆F₄O₄: C, 58.07; H, 4.33. Found: C, 58.00; H, 4.27. ¹H-NMR(CDCl₃)δ: 2.82-3.10 (3H, m), 4.29 (2H, q, J=8.0 Hz), 5.06 (1H, d, J=4.4Hz), 6.69 (1H, s), 6.70-7.02 (2H, m), 7.00-7.24 (3H, m), 7.30-7.44 (2H,m).

5) To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(2,2,2-trifluoroethoxy)phenyl)methyl)propionicacid (2.68 g, 7.20 mmol) in tetrahydrofuran (60 ml) were addeddiphenylphosphoryl azide (1.71 ml,7.92 mmol) and triethylamine (1.51 ml,10.8 mmol) and the mixture was heated under reflux for 3 hrs. Thereaction solution was allowed to stand at room temperature, water (200ml) was added, and the mixture was extracted with ethyl acetate (200ml×2). The extract was washed successively with 1N hydrochloric acid,saturated aqueous sodium hydrogen carbonate and saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was recrystallized from ethyl acetate-hexane to give(4RS,5SR)-5-(4-fluorophenyl)-4-((3-(2,2,2-trifluoroethoxy)phenyl)methyl)-1,3-oxazolidin-2-one(2.31 g, 87%).

mp 148-149° C. IR ν max^(KBr)cm⁻¹: 1759, 1609, 1590, 1514. Anal. Calcdfor C₁₈H₁₅F₄NO₃: C, 58.54; H, 4.09; N, 3.79. Found: C, 58.54; H, 4.01;N, 3.88. ¹H-NMR (CDCl₃)δ: 2.12-2.38 (2H, m), 4.16-4.28 (1H, m), 4.32(2H, q, J=8.0 Hz), 5.17 (1H, brs), 5.79 (1H, d, J=8.0 Hz), 6.62 (1H, d,J=1.8 Hz), 6.72 (1H, d, J=7.6 Hz), 6.77-6.84 (1H, m), 7.04-7.42 (5H, m).

6) To a solution of(4RS,5SR)-5-(4-fluorophenyl)-4-((3-(2,2,2-trifluoroethoxy)phenyl)methyl)-1,3-oxazolidin-2-one(1.2 g, 3.25 mmol) in ethanol (10 ml) was added 8N aqueous sodiumhydroxide solution (2.0 ml, 16 mmol) and the mixture was heated underreflux for 2 hrs. The reaction solution was concentrated, diluted withwater (100 ml) and extracted with ethyl acetate (100 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. The residue was recrystallizedfrom ethyl acetate-hexane to give(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(2,2,2-trifluoroethoxy)phenyl)-1-propanol(913 mg, 82%).

mp 94-95° C. IR ν max^(KBr)cm⁻¹: 1605, 1588, 1508, 1489, 1454 Anal.Calcd for C₁₇H₁₇F₄NO₂: C, 59.47; H, 4.99; N, 4.08. Found: C, 59.34; H,4.87; N, 4.19. ¹H-NMR (CDCl₃)δ: 2.33 (1H, dd, J=14.0, 10.6 Hz), 2.78(1H, dd, J=14.0, 3.0 Hz), 3.20-3.34 (1H, m), 4.33 (2H, q, J=8.0 Hz),4.66 (1H, d, J=4.6 Hz), 6.70-6.90 (3H, m), 7.00-7.16 (2H, m), 7.20-7.30(1H, m), 7.30-7.44 (2H, m).

7) To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(2,2,2-trifluoroethoxy)phenyl)-1-propanol(181 mg, 0.53 mmol) in acetonitrile (20 ml) were added4-fluoronaphthalenecarboxylic acid (100 mg, 0.53 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg,0.79 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to give the titlecompound (206 mg, 76%).

mp 192-193° C. IR ν max^(KBr)cm⁻¹: 1642, 1626, 1601, 1512. Anal. Calcdfor C₂₈H₂₂F₅NO₃.0.1H₂O: C, 65.02; H, 4.32; N, 2.71. Found: C, 64.89; H,4.43; N, 2.93. ¹H-NMR (CDCl₃)δ: 2.78 (1H, dd, J=14.6, 11.0 Hz), 3.04(1H, dd, J=14.6, 4.0 Hz), 4.28 (2H, q, J=8.0 Hz), 4.70-4.88 (1H, m),5.09 (1H, d, J=3.8 Hz), 5.90 (1H, d, J=8.8 Hz), 6.76-7.36 (8H, m),7.40-7.60 (4H, m), 7.77 (1H, d, J=7.6 Hz), 8.09 (1H, d, J=7.6 Hz).

Example 171N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((3-(2,2,2-trifluoroethoxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-1-(2-fluorophenyl)-3-(3-(2,2,2-trifluoroethoxy)phenyl)-1-propanol(183 mg, 0.53 mmol) in acetonitrile (20 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (100 mg, 0.53mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153mg, 0.80 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to give the titlecompound (225 mg, 82%).

mp 172-173° C. IR ν max^(KBr)cm⁻¹: 1636, 1605, 1588, 1510. ¹H-NMR(CDCl₃)δ: 1.90-2.08 (2H, m), 2.10-2.36 (2H, m), 2.60-2.80 (3H, m), 2.97(1H, dd, J=14.2, 4.0 Hz), 3.78 (1H, s), 4.30 (2H, q, J=8.2 Hz),4.60-4.76 (1H, m), 5.01 (1H, d, J=3.2 Hz), 5.75 (1H, d, J=8.4 Hz),5.82-6.00 (1H, m), 6.17 (1H, d, J=11.8 Hz), 6.77 (1H, s), 6.80-6.92 (1H,m), 6.94-7.30 (7H, m), 7.38-7.50 (2H, m).

Example 172N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((3-(2,2,3,3-tetrafluoropropyloxy)phenyl)methyl)ethyl)-4-fluoro-1-naphthalenecarboxamide

1) To a solution of 3-hydroxytoluene (5.0 g, 46.2 mmol) inN,N-dimethylformamide (50 ml) were added2,2,3,3-tetrafluoro-1-iodopropane (12.3 g, 50.9 mmol) and potassiumcarbonate (12.8 g, 92.5 mmol) and the mixture was stirred overnight at80° C. The reaction solution was diluted with water (200 ml) andextracted with diethyl ether (300 ml×2). The extract was washedsuccessively with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=10:1)to give 3-(2,2,3,3-tetrafluoropropyloxy)toluene (10.0 g, 97%) as acolorless oil.

IR ν max^(KBr)cm⁻¹: 1607, 1588, 1491, 1458. Anal. Calcd forC₁₀H₁₀F₄O.0.2H₂O: C, 53.20; H, 4.64 Found: C, 53.01; H, 4.40. ¹H-NMR(CDCl₃)δ: 2.34 (3H, s), 4.32 (2H, tt, J=12.0, 1.6 Hz), 6.07 (1H, tt,J=53.2, 5.0 Hz), 6.70-6.90 (3H, m), 7.16-7.24 (1H, m).

2) To a solution of 3-(2,2,3,3-tetrafluoropropyloxy)toluene (7.0 g, 31.5mmol) in carbon tetrachloride (100 ml) were added N-bromosuccinimide(6.17 g, 34.7 mmol) and 2,2′-azobis(isobutyronitrile) (517 mg, 3.15mmol) and the mixture was heated under reflux overnight. The insolublematerial was filtered using celite and the filtrate was concentrated toprepare a bromo form. To a solution of ethyl3-(4-fluorophenyl)-3-oxopropionate (5.96 g, 28.4 mmol) in1,2-dimethoxyethane (60 ml) was added sodium hydride (60% in oil, 1.13g, 28.4 mmol) under ice-cooling and the mixture was stirred at roomtemperature for 30 min. To the reaction solution was dropwise added asolution of the bromo form synthesized above in 1,2-dimethoxyethane (20ml) and the reaction solution was stirred at room temperature for 1 hr.The reaction solution was poured into water (200 ml) and extracted withethyl acetate (200 ml×2). The extract was washed with water andsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) and recrystallized fromdiisopropyl ether-hexane to give ethyl3-(4-fluorophenyl)-3-oxo-2-((3-(2,2,3,3-tetrafluoropropyloxy)phenyl)methyl)propionate(5.63 g, 46%).

mp 55-56° C. IR ν max^(KBr)cm⁻¹: 1738, 1688, 1599, 1508, 1489, 1449.Anal. Calcd for C₂₁H₁₉F₅O₄: C, 58.61; H, 4.45. Found: C, 58.50; H, 4.41.¹H-NMR (CDCl₃)δ: 1.13 (3H, t, J=7.2 Hz), 3.30 (2H, d, J=7.2 Hz), 4.11(2H, q, J=7.2 Hz), 4.20-4.38 (2H, m), 4.56 (1H, t, J=7.2 Hz), 6.05 (1H,tt, J=53.0, 5.0 Hz), 6.70-6.88 (2H, m), 6.91 (1H, d, J=7.2 Hz),7.06-7.30 (3H, m), 7.92-8.08 (2H, m).

3) To a solution of zinc chloride (3.50 g, 25.6 mmol) in diethyl ether(100 ml) was added sodium borohydride (1.93 g, 51.1 mmol) and themixture was stirred at room temperature for 30 min. The insolublematerial was filtered off. To the filtrate was added a solution of ethyl3-(4-fluorophenyl)-3-oxo-2-((3-(2,2,3,3-tetrafluoropropyloxy)phenyl)methyl)propionate(5.50 g, 12.8 mmol) in diethyl ether (50 ml) and the mixture was stirredat room temperature for 30 min. 1N Hydrochloric acid was added to thereaction solution under ice-cooling for quenching, water (200 ml) wasadded, and the mixture was extracted with ethyl acetate (300 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=4:1)to give ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(2,2,3,3-tetrafluoropropyloxy)phenyl)methyl)propionate(4.99 g, 90%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1725, 1605, 1588, 1511. Anal. Calcd for C₂₁H₂₁F₅O₄:C, 58.33; H, 4.90. Found: C, 58.20; H, 4.92. ¹H-NMR (CDCl₃)δ: 0.94 (3H,t, J=7.0 Hz), 2.89 (1H, d, J=2.8 Hz), 2.92-3.02 (3H, m), 3.90 (2H, q,J=7.0 Hz), 4.29 (2H, t, J=12.0 Hz), 5.02 (1H, s), 6.05 (1H, tt, J=53.0,5.0 Hz), 6.62-6.82 (3H, m), 7.00-7.24 (3H, m), 7.32-7.44 (2H, m).

4) To a solution of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(2,2,3,3-tetrafluoropropyloxy)phenyl)methyl)propionate(4.75 g, 11.0 mmol) in methanol (40 ml) was added 2N aqueous sodiumhydroxide solution (11 ml, 22.0 mmol) and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid and extracted with ethyl acetate (100 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from diisopropyl ether-hexane to give(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(2,2,3,3-tetrafluoropropyloxy)phenyl)methyl)propionicacid (3.91 g, 88%).

mp 114-115° C. IR ν max^(KBr)cm⁻¹: 1715, 1607, 1512. Anal. Calcd forC₁₉H₁₇F₅O₄: C, 56.44; H, 4.24. Found: C, 56.52; H, 4.35. ¹H-NMR(CDCl₃)δ: 2.84-3.08 (3H, m), 4.19-4.37 (2H, m), 5.06 (1H, d, J=4.4 Hz),6.04 (1H, tt, J=53.0, 5.0 Hz), 6.60-6.68 (1H, m), 6.68-6.80 (2H, m),7.00-7.30 (3H, m), 7.30-7.42 (2H, m).

5) To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(2,2,3,3-tetrafluoropropyloxy)phenyl)methyl)propionicacid (2.0 g, 4.95 mmol) in tetrahydrofuran (40 ml) were addeddiphenylphosphoryl azide (1.17 ml, 5.44 mmol) and triethylamine (1.04ml, 7.43 mmol) and the mixture was heated under reflux for 3 hrs. Thereaction solution was allowed to stand at room temperature, water (200ml) was added, and the mixture was extracted with ethyl acetate (200ml×2). The extract was washed successively with 1N hydrochloric acid,saturated aqueous sodium hydrogen carbonate and saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was recrystallized from ethyl acetate-hexane to give(4RS,5SR)-5-(4-fluorophenyl)-4-((3-(2,2,3,3-tetrafluoropropyloxy)phenyl)methyl)-1,3-oxazolidin-2-one(1.68 g, 85%).

mp 113-114° C. IR ν max^(KBr)cm⁻¹: 1759, 1608, 1588, 1514. Anal. Calcdfor C₁₉H₁₆F₅NO₃: C, 56.89; H, 4.02; N, 3.49. Found: C, 56.99; H, 4.15;N, 3.53. ¹H-NMR (CDCl₃)δ: 2.10-2.40 (2H, m), 4.18-4.40 (3H, m), 5.22(1H, brs), 5.79 (1H, d, J=8.4 Hz), 6.05 (1H, tt, J=53.2, 5.0 Hz), 6.59(1H, s), 6.66-6.82 (2H, m), 7.04-7.40 (5H, m).

6) To a solution of(4RS,5SR)-5-(4-fluorophenyl)-4-((3-(2,2,3,3-tetrafluoropropyloxy)phenyl)methyl)-1,3-oxazolidin-2-one(1.0 g, 2.49 mmol) in ethanol (10 ml) was added 8N aqueous sodiumhydroxide solution (1.56 ml, 12.5 mmol) and the mixture was heated underreflux for 3 hrs. The reaction solution was concentrated, diluted withwater (100 ml) and extracted with ethyl acetate (100 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. The residue was recrystallizedfrom ethyl acetate-hexane to give(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(2,2,3,3-tetrafluoropropyloxy)phenyl)-1-propanol(825 mg, 88%).

mp 77-78° C. IR ν max^(KBr)cm⁻¹: 1605, 1586, 1508, 1489. Anal. Calcd forC₁₈H₁₈F₅NO₂: C, 57.60; H, 4.83; N, 3.73. Found: C, 57.62; H, 4.70; N,3.76. ¹H-NMR (CDCl₃)δ: 2.33 (1H, dd, J=14.0, 10.4 Hz), 2.79 (1H, dd,J=14.0, 3.0 Hz), 3.22-3.34 (1H, m), 4.32 (2H, t, J=12.0 Hz), 4.66 (1H,d, J=4.8 Hz), 6.06 (1H, tt, J=53.0, 5.0 Hz), 6.70-6.90 (3H, m),7.00-7.14 (2H, m), 7.20-7.30 (1H, m), 7.30-7.44 (2H, m).

7) To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(2,2,3,3-tetrafluoropropyloxy)phenyl)-1-propanol(197 mg, 0.53 mmol) in acetonitrile (20 ml) were added4-fluoronaphthalenecarboxylic acid (100 mg, 0.53 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg,0.79 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to give the titlecompound (240 mg, 84%).

mp 160-161° C. IR ν max^(KBr)cm⁻¹: 1641, 1626, 1601, 1535, 1512. Anal.Calcd for C₂₉H₂₃F₆NO₃.0.2H₂O: C, 63.21; H, 4.28; N, 2.54. Found: C,62.99; H, 4.39; N, 2.84. ¹H-NMR (CDCl₃)δ: 2.79 (1H, dd, J=14.4, 10.6Hz), 3.04 (1H, dd, J=14.4, 4.0 Hz), 4.28 (2H, t, J=12.0 Hz), 4.70-4.84(1H, m), 5.10 (1H, d, J=4.0 Hz), 5.90 (1H, d, J=8.4 Hz), 6.01 (1H, tt,J=53.0, 5.0 Hz), 6.74-7.30 (8H, m), 7.40-7.60 (4H, m), 7.77 (1H, d,J=8.2 Hz), 8.09 (1H, d, J=7.6 Hz).

Example 173N-(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((3-(2,2,3,3-tetrafluoropropyloxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-1-(2-fluorophenyl)-3-(3-(2,2,3,3-tetrafluoropropyloxy)phenyl)-1-propanol(200 mg, 0.53 mmol) in acetonitrile (20 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (100 mg, 0.53mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153mg, 0.80 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to give the titlecompound (224 mg, 77%).

mp 169-170° C. IR ν max^(KBr)cm⁻¹: 1640, 1605, 1587, 1510. ¹H-NMR(CDCl₃)δ: 1.90-2.08 (2H, m), 2.10-2.28 (2H, m), 2.60-2.80 (3H, m), 2.97(1H, dd, J=14.6, 4.0 Hz), 3.77 (1H, brs), 4.30 (2H, t, J=12.0 Hz),4.58-4.76 (1H, m), 5.02 (1H, d, J=3.6 Hz), 5.70-5.82 (1H, m), 5.84-5.98(1H, m), 6.04 (1H, tt, J=53.0, 5.0 Hz), 6.17 (1H, d, J=12.0 Hz), 6.75(1H, s), 6.78-6.90 (2H, m), 6.90-7.30 (6H, m), 7.38-7.50 (2H, m).

Example 174

4-fluoro-N-((1RS,2SR)-2-hydroxy-2-phenyl-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

1) To a solution of ethyl 3-oxo-3-phenylpropionate (28.6 g, 145 mmol) in1,2-dimethoxyethane (1.50 ml) was added sodium hydride (60% in oil, 5.65g, 141 mmol) under ice-cooling and the mixture was stirred at roomtemperature for 1 hr. To the reaction solution was dropwise added asolution of 4-trifluoromethylbenzyl bromide (33.8 g, 141 mmol) in1,2-dimethoxyethane (50 ml) and the reaction solution was stirred atroom temperature for 2 hrs. The reaction solution was poured into water(500 ml) and extracted with ethyl acetate (500 ml×2). The extract waswashed with water and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (toluene) to give ethyl3-oxo-3-phenyl-2-((4-(trifluoromethyl)phenyl)methyl)propionate (45.4 g,75%) as a yellow oil.

IR ν max^(KBr)cm⁻¹: 1738, 1688. ¹H-NMR (CDCl₃)δ: 1.11 (3H, t, J=7.2 Hz),3.39 (2H, d, J=7.8 Hz), 4.10 (2H, q, J=7.2 Hz), 4.63 (1H, t, J=8.4 Hz),7.10-7.64 (7H, m), 7.96 (2H, d, J=8.4 Hz).

2) To a solution of zinc chloride (14.7 g, 108 mmol) in diethyl ether(250 ml) was added sodium borohydride (8.2 g, 216 mmol) and the mixturewas stirred at room temperature for 2 hrs. The insoluble material wasfiltered off. To the filtrate was added a solution of3-oxo-3-phenyl-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (22g, 54 mmol) in diethyl ether (50 ml) and the mixture was stirred at roomtemperature for 30 min. 1N Hydrochloric acid was added to the reactionsolution under ice-cooling for quenching, water (200 ml) was added, andthe mixture was extracted with ethyl acetate (300 ml×2). The extract waswashed with water and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (toluene) to give ethyl(2RS,3RS)-3-hydroxy-3-phenyl-2-((4-(trifluoromethyl)phenyl)methyl)propionate(15.6 g, 83%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1717. Anal. Calcd for C₁₉H₁₉F₃O₃: C, 64.77; H, 5.44.Found: C, 64.65; H, 5.67. ¹H-NMR (CDCl₃)δ: 0.91 (3H, t, J=7.2 Hz),2.96-3.10 (3H, m), 3.88 (2H, q, J=7.2 Hz), 5.00-5.08 (1H, m), 7.12-7.56(9H, m).

3) To a solution of ethyl(2RS,3RS)-3-hydroxy-3-phenyl-2-((4-(trifluoromethyl)phenyl)methyl)propionate(10.0 g, 28.4 mmol) in methanol (40 ml) was added 2N aqueous sodiumhydroxide solution (28.4 ml, 56.8 mmol) and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to give(2RS,3RS)-3-hydroxy-3-phenyl-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (7.87 g, 86%).

mp 138-139° C. IR ν max^(KBr)cm⁻¹: 1694. Anal. Calcd for C₁₇H₁₅F₃O₃: C,62.96; H, 4.66. Found: C, 62.90; H, 4.89. ¹H-NMR (CDCl₃)δ: 2.90-3.12(3H, m), 5.11 (1H, d, J=3.0 Hz), 7.17 (2H, d, J=8.0 Hz), 7.30-7.42 (5H,m), 7.46 (2H, d, J=8.0 Hz).

4) To a solution of(2RS,3RS)-3-hydroxy-3-phenyl-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (7 g, 21.6 mmol) in tetrahydrofuran (200 ml) were addeddiphenylphosphoryl azide (5.12 ml, 23.7 mmol) and triethylamine (4.5 ml,32.4 mmol) and the mixture was heated under reflux for 4 hrs. Thereaction solution was allowed to stand at room temperature, water (200ml) was added, and the mixture was extracted with ethyl acetate (200ml×2). The extract was washed successively with 1N hydrochloric acid,saturated aqueous sodium hydrogen carbonate and saturated brine, driedover anhydrous magnesium sulfate and evaporated-under reduced pressure.The residue was recrystallized from ethyl acetate-hexane to give(4RS,5SR)-5-phenyl-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(6.5 g, 93%).

mp 158-159° C. IR ν max^(KBr)cm⁻¹: 1732. Anal. Calcd for C₁₇H₁₄F₃NO₂: C,63.55; H, 4.39; N, 4.36. Found: C, 63.38; H, 4.60; N, 4.21. ¹H-NMR(CDCl₃)δ: 2.22-2.42 (1H, m), 2.37 (1H, s), 4.20-4.34 (1H, m), 5.05 (1H,s), 5.83 (1H, d, J=8.0 Hz), 7.14 (2H, d, J=8.0 Hz), 7.30-7.50 (5H, m),7.54 (2H, d, J=8.0 Hz).

5) To a solution of(4RS,5SR)-5-phenyl-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(6.0 g, 18.7 mmol) in ethanol (100 ml) was added 8N aqueous sodiumhydroxide solution (11.7 ml, 93 mmol) and the mixture was heated underreflux for 4 hrs. The reaction solution was concentrated, diluted withwater (300 ml) and extracted with ethyl acetate (300 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. The residue was recrystallizedfrom diisopropyl ether-hexane to give(1RS,2SR)-2-amino-1-phenyl-3-(4-(trifluoromethyl)phenyl)-1-propanol (4.8g, 87%).

mp 64-65° C. IR ν max^(KBr)cm⁻¹: 1584, 1331. Anal. Calcd for C₁₆H₁₆F₃NO:C, 65.08; H, 5.46; N, 4.74. Found: C, 65.05; H, 5.65; N, 4.62. ¹H-NMR(CDCl₃)δ: 2.45 (1H, dd, J=13.8, 10.2 Hz), 2.91 (1H, dd, J=13.8, 2.8 Hz),3.22-3.36 (1H, m), 4.65 (1H, d, J=5.0 Hz), 7.20-7.42 (7H, m), 7.53 (2H,d, J=8.0 Hz).

6) To a solution of(1RS,2SR)-2-amino-1-phenyl-3-(4-(trifluoromethyl)phenyl)-1-propanol (500mg, 1.69 mmol) in acetonitrile (30 ml) were added4-fluoronaphthalenecarboxylic acid (322 mg, 1.69 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (487 mg,2.54 mmol) and 1-hydroxy-1H-benzotriazole (259 mg, 1.69 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate). Recrystallization from ethyl acetate-hexane gave the titlecompound (650 mg, 84%).

mp 217-218° C. IR ν max^(KBr)cm⁻¹: 1644, 1626, 1601, 1537. Anal. Calcdfor C₂₇H₂₁F₄NO₂: C, 69.37; H, 4.53; N, 3.00. Found: C, 69.15; H, 4.59;N, 2.80. ¹H-NMR (CDCl₃)δ: 2.89 (1H, dd, J=14.2, 10.6 Hz), 3.02-3.20 (2H,m), 4.78-4.96 (1H, m), 5.13 (1H, d, J=3.8 Hz), 4.97 (1H, d, J=9.2 Hz),6.94-7.08 (1H, m), 7.10-7.70 (13H, m), 8.08 (1H, d, J=7.6 Hz).

Example 175N-((1RS,2SR)-2-hydroxy-2-phenyl-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-3-phenylpropanamide

To a solution of(1RS,2SR)-2-amino-1-phenyl-3-(4-(trifluoromethyl)phenyl)-1-propanol (500mg, 1.69 mmol) in ethyl acetate (15 ml) were added 3-phenylpropionylchloride; (377 ml, 2.54 mmol) and saturated aqueous sodium hydrogencarbonate (15 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (100 ml) andextracted with ethyl acetate (100 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was recrystallized from ethylacetate-hexane to give the title compound (628 mg, 87%).

mp 147-148° C. IR ν max^(KBr)cm⁻¹: 1632, 1547, 1537. Anal. Calcd forC₂₅H₂₄F₃NO₂: C, 70.24; H, 5.66; N, 3.28. Found: C, 70.28; H, 5.85; N,3.13. ¹H-NMR (CDCl₃)δ: 2.38 (2H, t, J=7.4 Hz), 2.60-2.80 (2H, m), 2.86(2H, t, J=7.4 Hz), 3.08 (1H, d, J=4.0 Hz), 4.38-4.50 (1H, m), 4.80-4.88(1H, m), 5.34 (1H, d, J=8.8 Hz), 7.04-7.40 (12H, m), 7.46 (2H, d, J=8.0Hz).

Example 1764-fluoro-N-((1RS,2SR)-2-(3-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

1) To a solution of 3-fluorobenzoic acid (25.5 g, 182 mmol) intetrahydrofuran (300 ml) was added 1,1′-carbonylbis-1H-imidazole (32.4g, 200 mmol) and the mixture was stirred at room temperature for 30 min.Monoethyl malonate magnesium salt (27.1 g, 94.7 mmol) was added to thereaction solution and the mixture was heated under reflux for 30 min.Ethyl acetate (50 ml) and water (50 ml) were added to the reactionsolution, and conc. hydrochloric acid was added until the aqueous layershowed acidic pH. The reaction solution was extracted with ethyl acetate(200 ml×2). The extract was washed with saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1) to give ethyl 3-(3-fluorophenyl)-3-oxopropionate (34.6 g,91%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1738, 1694, 1651, 1589. Anal. Calcd for C₁₁H₁₁FO₃:C, 62.85; H, 5.27. Found: C, 62.76; H, 5.24. ¹H-NMR (CDCl₃)δ: 1.26(9/4H, t, J=7.0 Hz), 1.34 (3/4H, t, J=7.0 Hz), 3.97 (6/4H, s), 4.18-4.32(2H, m), 5.66 (1/4H, s), 7.10-7.76 (4H, m).

2) To a solution of ethyl 3-(3-fluorophenyl)-3-oxopropionate (20 g, 95mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% inoil, 3.80 g, 95 mmol) under ice-cooling and the mixture was stirred atroom temperature for 30 min. To the reaction solution was dropwise addeda solution of 4-trifluoromethylbenzyl bromide (22.7 g, 95 mmol) in1,2-dimethoxyethane (50 ml) and the reaction solution was stirred atroom temperature for 4 hrs. The reaction solution was poured into water(300 ml) and extracted with ethyl acetate (500 ml×2). The extract waswashed with water and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (toluene:hexane=1:1-toluene) andrecrystallized from ethyl acetate-hexane to give ethyl3-(3-fluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate(28.8 g, 82%).

mp 50-51° C. IR ν max^(KBr)cm⁻¹: 1738, 1694, 1618, 1590. Anal. Calcd forC₁₉H₁₆F₄O₃: C, 61.96; H, 4.38. Found: C, 61.96; H, 4.33. ¹H-NMR(CDCl₃)δ: 1.12 (3H, t, J=7.0 Hz), 3.39 (2H, d, J=7.4 Hz), 4.12 (2H, q,J=7.0 Hz), 4.57 (1H, t, J=7.4 Hz), 7.22-7.80 (8H, m).

3) To a solution of zinc chloride (14.8 g, 108.6 mmol) in diethyl ether(150 ml) was added sodium borohydride (8.22 g, 217 mmol) and the mixturewas stirred at room temperature for 30 min. The insoluble material wasfiltered off. To the filtrate was added a solution of ethyl3-(3-fluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate(20 g, 54.3 mmol) in diethyl ether (50 ml), and the mixture was stirredat room temperature for 30 min. 1N Hydrochloric acid was added to thereaction-solution under ice-cooling for quenching, water (200 ml) wasadded, and the mixture was extracted with ethyl acetate (300 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethylacetate=2:1-1:1) to give ethyl(2RS,3RS)-3-(3-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate(19.4 g, 96%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1726, 1713, 1617, 1593. Anal. Calcd for C₁₉H₁₈F₄O₃:C, 61.62; H, 4.90. Found: C, 61.46; H, 4.83. ¹H-NMR (CDCl₃)δ: 0.94 (3H,t, J=7.0 Hz), 2.90-3.16 (4H, m), 3.91 (2H, q, J=7.0 Hz), 5.00-5.10 (1H,m), 6.92-7.40 (6H, m), 7.48 (2H, d, J=8.0 Hz).

4) To a solution of ethyl(2RS,3RS)-3-(3-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate(19 g, 51.3 mmol) in methanol (100 ml) was added 2N aqueous sodiumhydroxide solution (51 ml, 102 mmol) and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to give(2RS,3RS)-3-(3-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (15.6 g, 89%).

mp 128-129° C. IR ν max^(KBr)cm⁻¹: 1713, 1618, 1593. Anal. Calcd forC₁₇H₁₄F₄O₃: C, 59.65; H, 4.12. Found: C, 59.53; H, 3.85. ¹H-NMR(CDCl₃)δ: 2.87-3.17 (3H, m), 5.13 (1H, s), 6.90-7.42 (6H, m), 7.47 (2H,d, J=8.0 Hz).

5) To a solution of(2RS,3RS)-3-(3-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (10.0 g, 29.2 mmol) in tetrahydrofuran (250 ml) were addeddiphenylphosphoryl azide (6.9 ml, 32.1 mmol) and triethylamine (6.1 ml,43.8 mmol) and the mixture was heated under reflux for 4 hrs. Thereaction solution was allowed to stand at room temperature, water (200ml) was added, and the mixture was extracted with ethyl acetate (200ml×2). The extract was washed successively with 1N hydrochloric acid,saturated aqueous sodium hydrogen carbonate and saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was recrystallized from ethyl acetate-hexane to give(4RS,5SR)-5-(3-fluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(8.88 g, 90%).

mp 143-144° C. IR ν max^(KBr)cm⁻¹: 1761, 1618, 1593. Anal. Calcd forC₁₇H₁₃F₄NO₂: C, 60.18; H, 3.86; N, 4.13. Found: C, 60.06; H, 3.85; N,4.06. ¹H-NMR (CDCl₃)δ: 2.24-2.48 (2H, m), 4.20-4.36 (1H, m), 5.03 (1H,s), 5.81 (1H, d, J=7.6 Hz), 7.02-7.22 (5H, m), 7.36-7.50 (1H, m), 7.56(2H, d, J=8.0 Hz).

6) To a solution of(4RS,5SR)-5-(3-fluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(7.0 g, 20.6 mmol) in ethanol (100 ml) was added 8N aqueous sodiumhydroxide solution (12.9 ml, 103 mmol) and the mixture was heated underreflux for 4 hrs. The reaction solution was concentrated, diluted withwater (300 ml) and extracted with ethyl acetate (300 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. The residue was recrystallizedfrom ethyl acetate-hexane to give(1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(5.43 g, 84%).

mp 81-82° C. IR ν max^(KBr)cm⁻¹: 1616, 1590. Anal. Calcd for C₁₆H₁₅F₄NO:C, 61.34; H, 4.83; N, 4.47. Found: C, 61.31; H, 4.81; N, 4.37. ¹H-NMR(CDCl₃)δ: 0.80-1.70 (2H, br), 2.43 (1H, dd, J=13.6, 9.8 Hz), 2.83 (1H,dd, J=13.6, 2.8 Hz), 3.26-3.40 (1H, m), 4.69 (1H, d, J=4.8 Hz),6.94-7.08 (1H, m), 7.16 (2H, d, J=8.0 Hz), 7.20-7.42 (3H, m), 7.55 (2H,d, J=8.0 Hz).

7) To a solution of(1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in acetonitrile (20 ml) were added4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (412 mg,2.15 mmol) and 1-hydroxy-1H-benzotriazole (221 mg, 1.44 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to give the titlecompound (573 mg, 82%).

mp 200-201° C.

IR ν max^(KBr)cm⁻¹: 1644, 1626. Anal. Calcd for C₂₇H₂₀F₅NO₂.0.1H₂O: C,66.56; H, 4.18; N, 2.87. Found: C, 66.39; H, 3.99; N, 2.97. ¹H-NMR(CDCl₃)δ: 2.80-3.12 (2H, m), 3.20-3.50 (1H, br), 4.72-4.90 (1H, m), 5.15(1H, d, J=3.2 Hz), 6.02 (1H, d, J=8.0 Hz), 6.92-7.62 (12H, m), 7.67 (1H,d, J=8.0 Hz), 8.08 (1H, d, J=8.4 Hz).

Example 177N-((1RS,2SR)-2-(3-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(167 mg, 0.53 mmol) in acetonitrile (20 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (100 mg, 0.53mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153mg, 0.80 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to give the titlecompound (209 mg, 81%).

mp 151-152° C. IR ν max^(KBr)cm⁻¹: 1638, 1618, 1590, 1518, 1327. Anal.Calcd for C₂₈H₂₅F₄NO₂.0.2H₂O: C, 69.04; H, 5.25; N, 2.88. Found: C,68.98; H, 5.16; N, 2.94. ¹H-NMR (CDCl₃)δ: 1.90-2.10 (2H, m), 2.12-2.28(2H, m), 2.60-2.70 (2H, m), 2.84 (1H, dd, J=14.4, 10.6 Hz), 3.00 (1H,dd, J=15.0, 4.0 Hz), 3.61 (1H, brs), 4.60-4.80 (1H, m), 5.09 (1H, brs),5.82 (1H, d, J=8.2 Hz), 5.84-5.98 (1H, m), 6.16 (1H, d, J=11.6 Hz),6.92-7.42 (9H, m), 7.53 (2H, d, J=8.0 Hz).

Example 178N-((1RS,2SR)-2-(3-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-3-phenylpropanamide

To a solution of(1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in ethyl acetate (20 ml) were added3-phenylpropionyl chloride (320 ml, 2.15 mmol) and saturated aqueoussodium hydrogen carbonate (20 ml) and the mixture was stirred overnightat room temperature. The reaction solution was diluted with water (100ml) and extracted with ethyl acetate (100 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the title compound (528 mg, 83%).

mp 151-152° C. IR ν max^(KBr)cm⁻¹: 1651, 1620, 1590. Anal. Calcd forC₂₅H₂₃F₄NO₂: C, 67.41; H, 5.20; N, 3.14. Found: C, 67.38; H, 5.05; N,3.10. ¹H-NMR (CDCl₃)δ: 2.36-2.44 (2H, m), 2.60-2.76 (2H, m), 2.80-2.94(2H, m), 3.20-3.28 (1H, m), 4.30-4.48 (1H, m), 4.80-4.90 (1H, m), 5.35(1H, d, J=7.8 Hz), 6.92-7.40 (11H, m), 7.46 (2H, d, J=8.0 Hz).

Example 1794-fluoro-N-((1RS,2SR)-2-(2-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

1) To a solution of 2-fluorobenzoic acid (25.3 g, 181 mmol) intetrahydrofuran (300 ml) was added 1,1′-carbonylbis-1H-imidazole (32.2g, 198 mmol) and the mixture was stirred at room temperature for 30 min.To the reaction solution was added monoethyl malonate magnesium salt(27.1 g, 94.7 mmol) and the mixture was heated under reflux for 30 min.Ethyl acetate (50 ml) and water (50 ml) were added to the reactionsolution, and conc. hydrochloric acid was added until the aqueous layershowed acidic pH. The reaction solution was extracted with ethyl acetate(200 ml×2). The extract was washed with saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1) to give ethyl 3-(2-fluorophenyl)-3-oxopropionate (31.9 g,84%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1748, 1694, 1651, 1611. Anal. Calcd for C₁₁H₁₁FO₃:C, 62.85; H, 5.27. Found: C, 62.74; H, 5.24. ¹H-NMR (CDCl₃)δ: 1.26 (3H;t, J=7.2 Hz), 3.99 (8/5H, d, J=3.6 Hz), 4.18-4.30 (2H, m), 5.85 (1/5H,s); 7.06-7.32 (4H, m), 7.32-7.52 (2/5H, m), 7.52-7.64 (8/5H, m),7.82-8.02 (2H, m).

2) To a solution of ethyl 3-(2-fluorophenyl)-3-oxopropionate (20 g, 95mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% inoil, 3.80 g, 95 mmol) under ice-cooling and the mixture was stirred atroom temperature for 30 min. To the reaction solution was dropwise addeda solution of 4-trifluoromethylbenzyl bromide (22.7 g, 95 mmol) in1,2-dimethoxyethane (50 ml) and the reaction solution was stirred atroom temperature for 4 hrs. The reaction solution was poured into water(300 ml) and extracted with ethyl acetate (500 ml×2). The extract waswashed with water and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (toluene:hexane=1:1-toluene) to giveethyl3-(2-fluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate(25.7 g, 73%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1744, 1690. Anal. Calcd for C₁₉H₁₆F₄O₃: C, 61.96; H,4.38. Found: C, 62.04; H, 4.31. ¹H-NMR (CDCl₃)δ: 1.12 (3H, t, J=7.0 Hz),3.24-3.50 (2H, m), 4.12 (2H, q, J=7.0 Hz), 4.58 (1H, t, J=7.2 Hz),7.04-7.60 (7H, m), 7.78-7.90 (1H, m).

3) To a solution of zinc chloride (14.8 g, 108.6 mmol) in diethyl ether(150 ml) was added sodium borohydride (8.22 g, 217 mmol) and the mixturewas stirred at room temperature for 30 min. The insoluble material wasfiltered off. To the filtrate was added a solution of ethyl3-(2-fluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate(20 g, 54.3 mmol) in diethyl ether (50 ml) and the mixture was stirredat room temperature for 30 min. 1N Hydrochloric acid was added to thereaction solution under ice-cooling for quenching, water (200 ml wasadded, and the mixture was extracted with ethyl acetate (300 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethylacetate=9:1-4:1) to give ethyl(2RS,3RS)-3-(2-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate(16.2 g, 81%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1717, 1618, 1586. Anal. Calcd for C₁₉H₁₈F₄O₃: C,61.62; H, 4.90. Found: C, 61.51; H, 4.74. ¹H-NMR (CDCl₃)δ: 0.96 (3H, t,J=7.4 Hz), 2.84-3.20 (3H, m), 3.22 (1H, d, J=3.8 Hz), 3.94 (2H, q, J=7.4Hz), 5.30-5.40 (1H, m), 6.98-7.38 (5H, m), 7.40-7.62 (3H, m).

4) To a solution of ethyl(2RS,3RS)-3-(2-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate(15.7 g, 42.5 mmol) in methanol (100 ml) was added 2N aqueous sodium,hydroxide solution (43 ml, 86 mmol) and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to give(2RS,3RS)-3-(2-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (11.7 g, 80%).

mp 122-123° C. IR ν max^(KBr)cm⁻¹: 1713, 1491. Anal. Calcd forC₁₇H₁₄F₄O₃: C, 59.65; H, 4.12. Found: C, 59.60; H, 4.03. ¹H-NMR(CDCl₃)δ: 2.82-3.12 (2H, m), 3.12-3.30 (1H, m), 5.44 (1H, d, J=4.0 Hz),6.96-7.40 (5H, m), 7.40-7.60 (3H, m).

5) To a solution of(2RS,3RS)-3-(2-fluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (10.0 g, 29.2 mmol) in tetrahydrofuran (250 ml) were addeddiphenylphosphoryl azide (6.9 ml, 32.1 mmol) and triethylamine (6.1 ml,43.8 mmol) and the mixture was heated under reflux for 4 hrs. Thereaction solution was allowed to stand at room temperature, water (200ml) was added, and the mixture was extracted with ethyl acetate (200ml×2). The extract was washed successively with 1N hydrochloric acid,saturated aqueous sodium hydrogen carbonate and saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was recrystallized from ethyl acetate-hexane to give(4RS,5SR)-5-(2-fluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(8.73 g, 88%).

mp 146-147° C. IR ν max^(KBr)cm⁻¹: 1767. Anal. Calcd for Cl₇H₁₃F₄NO₂: C,60.18; H, 3.86; N, 4.13. Found: C, 59.99; H, 3.92; N, 3.90. ¹H-NMR(CDCl₃)δ: 2.20-2.60 (2H, m), 4.26-4.46 (1H, m), 5.06 (1H, s), 6.05 (1H,d, J=7.8 Hz), 7.00-7.70 (8H, m).

6) To a solution of(4RS,5SR)-5-(2-fluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(7.0 g, 20.6 mmol) in ethanol (100 ml) was added 8N aqueous sodiumhydroxide solution (12.9 ml, 103 mmol) and the mixture was heated underreflux for 6 hrs. The reaction solution was concentrated, diluted withwater (300 ml) and extracted with ethyl acetate (300 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate) to give(1RS,2SR)-2-amino-1-(2-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(6.2 g, 96%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1618, 1584, 1487. Anal. Calcd for C₁₆H₁₅F₄NO.0.1H₂O:C, 60.99; H, 4.86; N, 4.45. Found: C, 60.90; H, 4.81; N, 4.20. ¹H-NMR(CDCl₃)δ: 1.0-1.8 (2H, br), 2.41. (1H, dd, J=13.6, 11.0 Hz), 2.86 (1H,dd, J=14.0, 2.2 Hz), 3.36-3.48 (1H, m), 5.06 (1H, d, J=4.4 Hz),7.00-7.38 (5H, m), 7.48-7.62 (3H, m).

7) To a solution of(1RS,2SR)-2-amino-1-(2-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in acetonitrile (20 ml) were added4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (412 mg,2.15 mmol) and 1-hydroxy-1H-benzotriazole (221 mg, 1.44 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1). Recrystallization from ethyl acetate-hexane gave the titlecompound (465 mg, 67%).

mp 190-191° C. IR ν max^(KBr)cm⁻¹: 1645, 1628, 1601, 1537. Anal. Calcdfor C₂₇H₂₀F₅NO₂: C, 66.80; H, 4.15; N, 2.89. Found: C, 66.58; H, 4.12;N, 2.79. ¹H-NMR (CDCl₃)δ: 2.94 (1H, dd, J=14.2, 11.0 Hz), 3.23 (1H, dd,J=14.2, 4.0 Hz), 3.72 (1H, d, J=4.2 Hz), 4.74-4.94 (1H, m), 5.36-5.46(1H, m), 5.96 (1H, d, J=8.4 Hz), 6.96-7.74 (13H, m), 8.08 (1H, d, J=8.4Hz).

Example 180N-((1RS,2SR)-2-(2-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-3-phenylpropanamide

To a solution of(1RS,2SR)-2-amino-1-(2-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in ethyl acetate (20 ml) were added3-phenylpropionyl chloride (320 ml, 2.15 mmol) and saturated aqueoussodium hydrogen carbonate (20 ml) and the mixture was stirred overnightat room temperature. The reaction solution was diluted with water (100ml) and extracted with ethyl acetate (100 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the title compound (497 mg, 78%).

mp 124-125° C. IR ν max^(KBr)cm⁻¹: 1651, 1620, 1520. Anal. Calcd forC₂₅H₂₃F₄NO₂: C, 67.41; H, 5.20; N, 3.14. Found: C, 67.30; H, 5.19; N,2.89. ¹H-NMR (CDCl₃)δ: 2.30-2.42 (2H, m), 2.66-2.98 (4H, m), 3.92-4.04(1H, m), 4.28-4.46 (1H, m), 5.12-5.22 (1H, m), 5.39 (1H, d, J=8.8 Hz),6.98-7.40 (10H, m), 7.40-7.56 (3H, m).

Example 181N-((1RS,2SR)-2-(2,4-difluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-fluoro-1-naphthalenecarboxamide

1) To a solution of 2,4-difluorobenzoic acid (10 g, 63.3 mmol) intetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole (11.3g, 69.6 mmol) and the mixture was stirred at room temperature for 30min. Monoethyl malonate magnesium salt (10 g, 34.8 mmol) was added tothe reaction solution and the mixture was stirred at room temperaturefor 2 hrs. To the reaction solution were added ethyl acetate (50 ml) andwater (50 ml), and conc. hydrochloric acid was added until the aqueouslayer showed acidic pH. The reaction solution was extracted with ethylacetate (200 ml×2). The extract-was washed with saturated brine,dried-over anhydrous magnesium sulfate and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1) to give ethyl3-(2,4-difluorophenyl)-3-oxopropionate (9.85 g, 74%) as a brown oil.

IR ν max^(KBr)cm⁻¹: 1746, 1690, 1615, 1507. Anal. Calcd forC₁₁H₁₀O₃F₂.0.1H₂O: C, 57.45; H, 4.47. Found: C, 57.56; H, 4.48. ¹H-NMR(CDCl₃)δ: 1.26 (3H×5/6, t, J=7.4 Hz), 1.34 (3H×1/6, t, J=7.4 Hz), 3.96(2H×5/6, d, J=4.0 Hz), 4.18-4.32 (2H, m), 5.80 (1H×1/6, s), 6.80-7.06(2H, m), 7.80-8.06 (1H, m).

2) To a solution of ethyl 3-(2,4-difluorophenyl)-3-oxopropionate (9 g,39.4 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60%in oil, 1.58 g, 39.4 mmol) under ice-cooling and the mixture was stirredat room temperature for 30 min. To the reaction solution was dropwiseadded a solution of 4-trifluoromethylbenzyl bromide (9.43 g, 39.4 mmol)in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred atroom temperature for 3 hrs. The reaction solution was poured into water(200 ml) and extracted with ethyl acetate (200 ml×2). The extract waswashed with water and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced-pressure. The residue was purifiedby silica gel column chromatography (toluene:hexane=1:1-toluene) andrecrystallized from diisopropyl ether-hexane to give ethyl3-(2,4-difluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate(11.6 g, 77%).

mp 34-35° C. IR ν max^(KBr)cm⁻¹: 1742, 1690, 1613, 1593, 1499, 1429.Anal. Calcd for C₁₉H₁₅O₃F₅: C, 59.07; H, 3.91. Found: C, 58.86; H, 3.67.¹H-NMR (CDCl₃)δ: 1.13 (3H, t, J=7.4 Hz), 3.22-3.50 (2H, m), 4.13 (2H, q,J=7.4 Hz), 4.53 (1H, t, J=7.2 Hz), 6.80-7.02 (2H, m), 7.38 (2H, d, J=8.0Hz), 7.52 (2H, d, J=8.0 Hz), 7.82-8.00 (1H, m).

3) To a solution of zinc chloride (7.06 g, 51.8 mmol) in *diethyl ether(100 ml) was added sodium borohydride (3.92 g, 103.5 mmol) and themixture was stirred at room temperature for 30 min. The insolublematerial was filtered off. To the filtrate was added a solution of ethyl3-(2,4-difluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate(10 g, 25.9 mmol) in diethyl ether (50 ml) and the mixture was stirredat room temperature for 30 min. 1N Hydrochloric acid as added to thereaction solution under ice-cooling for quenching, water (200 ml) wasadded, and the mixture was extracted with ethyl acetate (300 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=4:1)to give ethyl(2RS,3RS)-3-(2,4-difluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate(8.23 g, 82%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1713, 1618, 1505, 1420. Anal. Calcd forC₁₉H₁₇O₃F₅.0.2H₂O: C, 58.23; H, 4.47. Found: C, 58.04; H, 4.60. ¹H-NMR(CDCl₃)δ: 0.97 (3H, t, J=7.0 Hz), 2.80-3.18 (3H, m), 3.25 (1H, d, J=3.6Hz), 3.95 (2H, q, J=7.0 Hz), 5.28-5.38 (1H, m), 6.72-7.00 (2H, m), 7.18(2H, d, J=8.0 Hz), 7.48 (2H, d, J=8.0 Hz), 7.40-7.60 (1H, m).

4) To a solution of ethyl(2RS,3RS)-3-(2,4-difluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate(8.1 g, 20.8 mmol) in methanol (40 ml) was added 2N aqueous sodiumhydroxide solution (20.8 ml, 41.6 mmol) and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to give(2RS,3RS)-3-(2,4-difluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (6.0 g, 80%).

mp 120-121° C. IR ν max^(KBr)cm⁻¹: 1713, 1620, 1505, 1418. Anal. Calcdfor C₁₇H₁₃O₃F₅: C, 56.57; H, 3.64. Found: C, 56.68; H, 3.59. ¹H-NMR(CDCl₃)δ: 2.84-3.24 (3H, m), 5.38 (1H, d, J=4.0 Hz), 6.70-6.98 (2H, m),7.16 (2H, d, J=8.0 Hz), 7.46 (2H, d, J=8.0 Hz), 7.50-7.58 (1H, m).

5) To a solution of(2RS,3RS)-3-(2,4-difluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (5.0 g, 13.9 mmol) in tetrahydrofuran (150 ml) were addeddiphenylphosphoryl azide (3.3 ml, 15.3 mmol) and triethylamine (2.9 ml,20.8 mmol) and the mixture was heated under reflux for 6 hrs. Thereaction solution was allowed to stand at room temperature, water (200ml) was added, and the mixture was extracted with ethyl acetate (200ml×2). The extract was washed successively with 1N hydrochloric acid,saturated aqueous sodium hydrogen carbonate and saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate). The residue was recrystallized from ethyl acetate-hexane togive(4RS,5SR)-5-(2,4-difluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(3.86 g, 78%).

mp 147-148° C. IR ν max^(KBr)cm⁻¹: 1767, 1622, 1607, 1507. Anal. Calcdfor C₁₇H₁₂O₂F₅N: C, 57.15; H, 3.39; N, 3.92. Found: C, 57.12; H, 3.12;N, 3.63. ¹H-NMR (CDCl₃)δ: 2.24-2.56 (2H, m), 4.28-4.44 (1H, m), 5.12(1H, s), 5.99 (1H, d, J=7.6 Hz), 6.78-6.92 (1H, m), 6.92-7.08 (1H, m),7.17 (2H, d, J=7.6 Hz), 7.50-7.64 (3H, m).

6) To a solution of(4RS,5SR)-5-(2,4-difluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(3.5 g, 9.8 mmol) in ethanol (60 ml) was added 8N aqueous sodiumhydroxide solution (6.1 ml, 49 mmol) and the mixture was heated underreflux for 6 hrs. The reaction solution was concentrated, diluted withwater (300 ml) and extracted with ethyl acetate (300 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. The residue was recrystallizedfrom ethyl acetate-hexane to give(1RS,2SR)-2-amino-1-(2,4-difluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(2.27 g, 70%).

mp 99-100° C. IR ν max^(KBr)cm⁻¹: 1618, 1501, 1427, 1420. Anal. Calcdfor C₁₆H₁₄OF₅N: C, 58.01; H, 4.26; N, 4.23. Found: C, 58.09; H, 4.14; N,4.07. ¹H-NMR (CDCl₃)δ: 2.39 (1H, dd, J=14.0, 10.6 Hz), 2.83 (1H, dd,J=14.0, 3.0 Hz), 3.36-3.48 (1H, m), 5.01 (1H, d, J=4.4 Hz), 6.78-7.00(2H, m), 7.24 (2H, d, J=8.0 Hz), 7.54 (2H, d, J=8.0 Hz), 7.50-7.62 (1H,m).

7) To a solution of(1RS,2SR)-2-amino-1-(2,4-difluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(400 mg, 1.21 mmol) in acetonitrile (30 ml) were added4-fluoronaphthalenecarboxylic acid (230 mg, 1.21 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (347 mg,1.81 mmol) and 1-hydroxy-1H-benzotriazole (185 mg, 1.21 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to give the titlecompound (538 mg, 89%).

mp 194-195° C. IR ν max^(KBr)cm⁻¹: 1645, 1622, 1601, 1537, 1507. Anal.Calcd for C₂₇H₁₉O₂F₆N: C, 64.42; H, 3.80; N, 2.78. Found: C, 64.14; H,3.59; N, 2.63. ¹H-NMR (CDCl₃)δ: 2.92 (1H, dd, J=14.6, 11.2 Hz), 3.19(1H, dd, J=14.6, 3.8 Hz), 3.88 (1H, brs), 4.70-4.88 (1H, m), 5.33 (1H,d, J=4.0 Hz), 5.96 (1H, d, J=8.8 Hz), 6.78-7.18 (4H, m), 7.22-7.70 (8H,m), 8.08 (1H, d, J=8.4 Hz).

Example 182N-((1RS,2SR)-2-(2,4-difluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-3-phenylpropanamide

To a solution of(1RS,2SR)-2-amino-1-(2,4-difluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(400 mg, 1.21 mmol) in ethyl acetate (20 ml) were added3-phenylpropionyl chloride (269 ml, 1.81 mmol) and saturated aqueoussodium hydrogen carbonate (20 ml) and the mixture was stirred overnightat room temperature. The reaction solution was diluted with water (100ml) and extracted with ethyl acetate (100 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the title compound (498 mg, 89%).

mp 126-127° C. IR ν max^(KBr)cm⁻¹: 1645, 1620, 1503, 1427. Anal. Calcdfor C₂₅H₂₂O₂F₅N: C, 64.79; H, 4.78; N, 3.02. Found: C, 64.82; H, 4.57;N, 2.86. ¹H-NMR (CDCl₃)δ: 2.30-2.46 (2H, m), 2.64-2.92 (4H, m), 4.11(1H, d, J=4.0 Hz), 4.22-4.38 (1H, m), 5.04-5.14 (1H, m), 5.39 (1H, d,J=8.0 Hz), 6.70-6.92 (2H, m), 7.02-7.52 (10H, m).

Example 183N-((1RS,2SR)-2-(3,4-difluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-fluoro-1-naphthalenecarboxamide

1) To a solution of 3,4-difluorobenzoic acid (10 g, 63.3 mmol) intetrahydrofuran (300 ml) was added 1,1′-carbonylbis-1H-imidazole (11.3g, 69.6 mmol) and the mixture was stirred at room temperature for 30min. To the reaction solution was added monoethyl malonate magnesiumsalt (10 g, 34.8 mmol) and the mixture was stirred at room temperaturefor 2 hrs. To the reaction solution were added ethyl acetate (50 ml) andwater (50 ml), and conc. hydrochloric acid was added until the aqueouslayer showed acidic pH. The reaction solution was extracted with ethylacetate (200 ml×2). The extract was washed with saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1) to give ethyl3-(3,4-difluorophenyl)-3-oxopropionate (10.3 g, 77%) as a brown oil.

IR ν max^(KBr)cm⁻¹: 1742, 1694, 1613, 1520, 1433. Anal. Calcd forC₁₁H₁₀O₃F₂: C, 57.90; H, 4.42. Found: C, 57.78; H, 4.56. ¹H-NMR(CDCl₃)δ: 1.26 (3H×4/5, t, J=7.4 Hz), 1.33 (3H×1/5, t, J=7.4 Hz), 3.94(2H×4/5, s), 4.10-4.32 (2H, m), 5.60 (1H×1/5, s), 7.12-7.34 (1H, m),7.48-7.86 (2H, m).

2) To a solution of ethyl 3-(3,4-difluorophenyl)-3-oxopropionate (9 g,39.4 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60%in oil, 1.58 g, 39.4 mmol) under ice-cooling and the mixture was stirredat room temperature for 30 min. To the reaction solution was dropwiseadded a solution of 4-trifluoromethylbenzyl bromide (9.43 g, 39.4 mmol)in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred atroom temperature for 3 hrs. The reaction solution was poured into water(200 ml) and extracted with ethyl acetate (200ml×2). The extract waswashed with water and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (toluene:hexane=1:1) andrecrystallized from diisopropyl ether-hexane to give ethyl3-(3,4-difluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate(10.9 g, 71%).

mp 48-49° C. IR ν max^(KBr)cm⁻¹: 1738, 1694, 1615, 1518, 1429. Anal.Calcd for C₁₉H₁₅O₃F₅: C, 59.07; H, 3.91. Found: C, 59.06; H, 3.87.¹H-NMR (CDCl₃)δ: 1.30 (3H, t, J=7.2 Hz), 3.38 (2H, d, J=7.2 Hz), 4.11(2H, q, J=7.2 Hz), 4.53 (1H, t, J=7.2 Hz), 7.16-7.30 (1H, m), 7.34 (2H,d, J=8.0 Hz), 7.53 (2H, d, J=8.0 Hz), 7.70-7.90 (2H, m).

3) To a solution of zinc chloride (7.06 g, 51.8 mmol) in diethyl ether.(100 ml) was added sodium borohydride (3.92 g, 103.5 mmol) and themixture was stirred at room temperature for 30 min. The insolublematerial was filtered off. To the filtrate was added a solution of ethyl3-(3,4-difluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate(10 g, 25.9 mmol) in diethyl ether (50 ml) and the mixture was stirredat room temperature for 30 min. 1N Hydrochloric acid was added to thereaction solution under ice-cooling for quenching, water (200 ml) wasadded, and the mixture was extracted with ethyl acetate (300 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=4:1)to give ethyl(2RS,3RS)-3-(3,4-difluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate(9.84 g, 98%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1715, 1620, 1520, 1435. Anal. Calcd forC₁₉H₁₇O₃F₅.0.2H₂O: C, 58.23; H, 4.47. Found: C, 58.07; H, 4.41. ¹H-NMR(CDCl₃)δ: 0.95 (3H, t, J=7.2 Hz), 2.86-3.12 (4H, m), 3.91 (2H, q, J=7.2Hz), 5.00-5.05 (1H, m), 7.04-7.34 (5H, m), 7.49 (2H, d, J=8.0 Hz).

4) To a solution of ethyl(2RS,3RS)-3-(3,4-difluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate(9.7 g, 25.0 mmol) in methanol (40 ml) was added 2N aqueous sodiumhydroxide solution (25 ml, 50.0 mmol) and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to give(2RS,3RS)-3-(3,4-difluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (6.7 g, 74%).

mp 76-77° C. IR ν max^(KBr)cm⁻¹: 1713, 1620, 1520, 1435. ¹H-NMR(CDCl₃)δ: 2.90-3.18 (3H, m), 5.07 (1H, s), 7.04-7.34 (5H, m), 7.49 (2H,d, J=8.0 Hz).

5) To a solution of(2RS,3RS)-3-(3,4-difluorophenyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (5.0 g, 13.9 mmol) in tetrahydrofuran (150 ml) were addeddiphenylphosphoryl azide (3.3 ml, 15.3 mmol) and triethylamine (2.9 ml,20.8 mmol) and the mixture was heated under reflux for 6 hrs. Thereaction solution was allowed to stand at room temperature, water (200ml) was added, and the mixture was extracted with ethyl acetate (200ml×2). The extract was washed successively with 1N hydrochloric acid,saturated aqueous sodium hydrogen carbonate and saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate). The residue was recrystallized from ethyl acetate-hexane togive(4RS,5SR)-5-(3,4-difluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(3.81 g, 77%).

mp 157-158° C. IR ν max^(KBr)cm⁻¹: 1761, 1617, 1524. Anal. Calcd forC₁₇H₁₂O₂F₅N: C, 57.15; H, 3.39; N, 3.92. Found: C, 57.12; H, 3.26; N,3.76. ¹H-NMR (CDCl₃)δ: 2.24-2.44 (2H, m), 4.20-4.38 (1H, m), 5.31 (1H,s), 5.76 (1H, d, J=7.6 Hz), 7.04-7.30 (5H, m), 7.55 (2H, d, J=8.0 Hz).

6) To a solution of(4RS,5SR)-5-(3,4-difluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(3.5 g, 9.8 mmol) in ethanol (60 ml) was added 8N aqueous sodiumhydroxide solution (6.1 ml, 49 mmol) and the mixture was heated underreflux for 6 hrs. The reaction solution was concentrated, diluted withwater (300 ml), and extracted with ethyl acetate (300 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. The residue was recrystallizedfrom ethyl acetate-hexane to give(1RS,2SR)-2-amino-1-(3,4-difluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(2.43 g, 75%).

mp 99-100° C. IR ν max^(KBr)cm⁻¹: 1618, 1576, 1518, 1429. Anal. Calcdfor C₁₆H₁₄OF₅N: C, 58.01; H, 4.26; N, 4.23. Found: C, 58.01; H, 3.97; N,4.05. ¹H-NMR (CDCl₃)δ: 2.41 (1H, dd, J=14.0, 10.4 Hz), 2.79 (1H, dd,J=14.0, 3.0 Hz), 3.22-3.36 (1H, m), 4.66 (1H, d, J=4.8 Hz), 7.04-7.32(5H, m), 7.55 (2H, d, J=8.2 Hz).

7) To a solution of(1RS,2SR)-2-amino-1-(3,4-difluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(400 mg, 1.21 mmol) in acetonitrile (30 ml) were added4-fluoronaphthalenecarboxylic acid (230 mg, 1.21 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (347 mg,1.81-mmol) and 1-hydroxy-1H-benzotriazole (185 mg, 1.21 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to give the titlecompound (522 mg, 86%).

mp 197-198° C. IR ν max^(KBr)cm⁻¹: 1642, 1626, 1601, 1522, 1424. Anal.Calcd for C₂₇H₁₉O₂F₆N: C, 64.42; H, 3.80; N, 2.78. Found: C, 64.20; H,3.68; N, 2.69. ¹H-NMR (CDCl₃)δ: 2.80-3.10 (2H, m), 4.64-4.84 (1H, m),5.06-5.18 (1H, m), 6.01 (1H, d, J=8.8 Hz), 6.94-7.72 (12H, m), 8.09 (1H,d, J=8.8 Hz).

Example 184N-((1RS,2SR)-2-(3,4-difluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-3-phenylpropanamide

To a solution of(1RS,2SR)-2-amino-1-(3,4-difluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(400 mg, 1.21 mmol) in ethyl acetate. (20 ml) were added3-phenylpropionyl chloride (269 ml, 1.81 mmol) and saturated aqueoussodium hydrogen carbonate (20 ml) and the mixture was stirred overnightat room temperature. The reaction solution was diluted with water (100ml) and extracted with ethyl acetate (100 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the title compound (471 mg, 84%).

mp 114-115° C. IR ν max^(KBr)cm⁻¹: 1647, 1620, 1518, 1433. Anal. Calcdfor C₂₅H₂₂O₂F₅N: C, 64.79; H, 4.78; N, 3.02. Found: C, 64.88; H, 4.59;N, 2.90. ¹H-NMR (CDCl₃)δ: 2.26-2.50 (2H, m), 2.58-2.80 (2H, m),2.82-2.96 (2H, m), 3.36 (1H, brs), 4.22-4.40 (1H, m), 4.81 (1H, d, J=2.6Hz), 5.34 (1H, d, J=7.2 Hz), 6.98-7.38 (10H, m), 7.47 (2H, d, J=8.0 Hz).

Example 185N-((1RS,2SR)-2-hydroxy-2-(1-naphthalenyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

1) To a solution of 1′-acetonaphthone (28.29 g, 0.1662 mmol) and ethanol(0.5 ml) in diethyl carbonate (200 ml) was added sodium hydride (13.3 g,60% in oil, 0.332 mol) by small portions and the mixture was stirred at80° C. for 1.5 hrs. The reaction solution was poured into water,acidified with dilute hydrochloric acid and extracted twice with ethylacetate. The extract was washed with water, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethylacetate=20:1-6:1) to give ethyl (1-naphthoyl)acetate (38.14 g, 95%) as ayellow liquid.

¹H-NMR (CDCl₃, 200M Hz) δ 1.21 (2.4H, t, J=7.2 Hz), 1.36 (0.6H, t, J=7.1Hz), 4.11 (1.6H, s), 4.20 (1.6H, q, J=7.2 Hz), 4.31 (0.4H, q, J=7.1 Hz),5.50 (0.2H, s), 7.44-7.67 (4H, m), 7.86-7.95 (2H, m), 8.03 (1H, d, J=8.0Hz), 8.75 (1H, d, J=8.4 Hz); IR (neat) 1740, 1682, 1315, 1211, 802, 775cm⁻¹

2) To a solution of ethyl (1-naphthoyl)acetate (10.2 g, 39.9 mmol) inacetonitrile (100 ml) was added 4-(trifluoromethyl)benzyl bromide (9.54g, 39.9 mmol) and the mixture was stirred overnight at room temperature.The reaction solution was concentrated, diluted with water (500 ml) andextracted with ethyl acetate (300 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:toluene=1:1). To a solution of the crude productof the obtained monoalkyl form (7.46 g, 18.63 mmol) in ether (100 ml)was added a solution of Zn(NH₄)₂ in ether (100 ml), which was preparedfrom zinc chloride (5.07 g, 37.3 mmol) and sodium borohydride (2.82 g,74.5 mmol), and the mixture was stirred at room temperature for 30 min.The reaction solution was ! poured into 1N aqueous hydrochloric acidsolution (100 ml) and extracted with ethyl acetate (300 ml×2). Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (toluene). To a solution of thecrude product of the obtained reduced compound (3.74 g, 9.29 mmol) inmethanol (40 ml) was added 1N aqueous sodium hydroxide solution (20 ml,20 mmol) and the mixture was stirred at room temperature for 4 hrs. Thereaction solution was poured into 1N aqueous hydrochloric acid solution(40 ml) and extracted with ethyl acetate (100 ml×2). The extract waswashed with saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromdiisopropyl ether-hexane to give(2RS,3RS)-3-hydroxy-3-(1-naphthalenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (2.48 g, 16%).

mp 151-152° C. IR ν max^(KBr)cm⁻¹: 1713. Anal. Calcd forC₂₁H₁₇F₃O₃.0.1H₂O: C, 67.05; H, 4.61. Found: C, 67.02; H, 4.45. ¹H-NMR(CDCl₃)δ: 2.87 (1H, d, J=14.0 Hz), 3.10-3.40 (2H, m), 6.04 (1H, d, J=2.8Hz), 6.98 (2H, d, J=8.0 Hz), 7.34 (2H, d, J=8.0 Hz), 7.42-7.62 (3H, m),7.72-7.98 (3H, m), 8.03 (1H, d, J=9.2 Hz).

3) To a solution of(2RS,3RS)-3-hydroxy-3-(1-naphthalenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (2.64 g, 7.05 mmol) in tetrahydrofuran (50 ml) were addeddiphenylphosphoryl azide (1.67 ml, 7.76 mmol) and triethylamine (1.5 ml,10.6 mmol) and the mixture was heated under reflux for 1 hr. Thereaction solution was diluted with water (300 ml) and extracted withethyl acetate (200 ml×2). The extract was washed with saturated brine,dried over anhydrous magnesium sulfate and evaporated under reduced,pressure. The residue was recrystallized from ethyl acetate-hexane togive(4RS,5SR)-5-(1-naphthalenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(2.19 g, 84%).

mp 202-203° C. IR ν max^(KBr)cm⁻¹: 1761. Anal. Calcd for C₂₁H₁₆F₃NO₂: C,67.92; H, 4.34; N, 3.77. Found: C, 67.90; H, 4.15; N, 3.63. ¹H-NMR(CDCl₃)δ: 2.15 (1H, dd, J=13.6, 4.4 Hz), 2.37 (1H, dd, J=13.6, 10.2 Hz),4.46-4.64 (1H, m), 5.38 (1H, brs), 6.53 (1H, d, J=7.6 Hz), 6.97 (2H, d,J=8.0 Hz), 7.39 (2H, d, J=8.0 Hz), 7.46-7.80 (4H, m), 7.80-8.00 (3H, m).

4) To a solution of(4RS,5SR)-5-(1-naphthalenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(2.10 g, 5.66 mmol) in ethanol (30 ml) was added 8N aqueous sodiumhydroxide solution (3.53 ml, 28.3 mmol) and the mixture was heated underreflux for 1 hr. The reaction solution was concentrated, diluted withwater (100 ml) and extracted with ethyl acetate (100 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under-reduced pressure. To a solution of the residue inethyl acetate (100 ml) was added a solution of HCl in ethyl acetate andthe solvent was concentrated. The obtained crude crystals were washedwith ether to give(1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (1.56 g, 72%).

mp 229-230° C. IR ν max^(KBr)cm⁻¹: 1761. Anal. Calcd forC₂₀H₁₉ClF₃NO.0.1H₂O: C, 62.62; H, 5.04; N, 3.65. Found: C, 62.44; H,5.07; N, 3.88. ¹H-NMR (CD₃OD)δ: 2.80-3.04 (2H, m), 3.96-4.10 (1H, m),5.93 (1H, d, J=2.6 Hz), 7.02 (2H, d, J=8.0 Hz), 7.37 (2H, d, J=8.0 Hz),7.46-7.62 (3H, m), 7.78-7.96 (3H, m), 8.07 (1H, d, J=8.0 Hz).

5) A solution of(1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) were added1-naphthoyl chloride (89 ml, 0.59 mmol) and saturated aqueous sodiumhydrogen carbonate (5 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (50 ml) andextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was recrystallized from ethylacetate-hexane to give the title compound (172 mg, 88%).

mp 217-218° C. IR ν max^(KBr)cm⁻¹: 1615, 1591, 1537, 1526. Anal. Calcdfor C₃₁H₂₄F₃NO₂: C, 74.54; H, 4.84; N; 2.80. Found: C, 74.33; H, 4.96;N, 2.76. ¹H-NMR (CDCl₃)δ: 2.80-3.14 (3H, m), 4.94-5.12 (1H, m), 6.04(1H, brs), 6.32 (1H, d, J=8.8 Hz), 7.17 (2H, d, J=8.2 Hz), 7.20-8.00(15H, m), 8.45 (1H, d, J=8.4 Hz).

Example 186

4-fluoro-N-((1RS,2SR)-2-hydroxy-2-(1-naphthalenyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

To a solution of 4-fluoronaphthalene-1-carboxylic acid (112 mg, 0.59mmol) in tetrahydrofuran (5 ml) were added oxalyl chloride (0.10 ml,1.18 mmol) and N,N-dimethylformamide (0.01 ml) and the mixture wasstirred at room temperature for 30 min. The reaction solution wasevaporated under reduced pressure. To a solution of the residue in ethylacetate (5 ml) were added(1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.39 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (50 ml) andextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1). Recrystallization from ethylacetate-hexane gave the title compound (147 mg, 72%).

mp 195-196° C. IR ν max^(KBr)cm⁻¹: 1644, 1620, 1514. Anal. Calcd forC₃₁H₂₃F₄NO₂: C, 71.95; H, 4.48; N, 2.71. Found: C, 71.67; H, 4.63; N,2.56; ¹H-NMR (CDCl₃)δ: 2.78 (1H, d, J=3.0 Hz), 2.80-3.16 (2H, m),4.96-5.14 (1H, m), 6.05 (1H, s), 6.27 (1H, d, J=8.8 Hz), 6.98-7.10 (1H,m), 7.14-7.30 (3H, m), 7.40-8.00 (11H, m), 8.09 (1H, d, J=8.4 Hz), 8.44(1H, d, J=8.4 Hz).

Example 187N-((1RS,2SR)-2-hydroxy-2-(1-naphthalenyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-2-naphthalenecarboxamide

To a solution of(1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) were added2-naphthoyl chloride (112 mg, 0.59 mmol) and saturated aqueous sodiumhydrogen carbonate (5 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution diluted with water (50 ml) andextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder-reduced pressure. The residue was recrystallized from ethylacetate-hexane to give the title compound (160 mg, 82%).

mp 251-252° C. IR ν max^(KBr)cm⁻¹: 1644, 1620. Anal. Calcd forC₃₁H₂₄F₃NO₂: C, 74.54; H, 4.84; N, 2.80. Found: C, 74.25; H, 4.56; N,2.75. ¹H-NMR (CDCl₃)δ: 2.82-3.30 (3H, m), 4.80-5.00 (1H, m), 6.08 (1H,s), 6.59 (1H, d, J=7.4 Hz), 7.15 (2H, d, J=8.2 Hz), 7.40 (2H, d, J=8.2Hz), 7.50-7.80 (6H, m), 7.80-7.98 (6H, m), 8.12 (1H, s), 8.45 (1H, d,J=8.4 Hz).

Example 188

4-fluoro-N-((1RS,2SR)-2-hydroxy-2-(1-naphthalenyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)benzamide

To a solution of(1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) were added4-fluorobenzoyl chloride (70 ml, 0.59 mmol) and saturated aqueous sodiumhydrogen carbonate (5 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (50 ml) andextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was recrystallized from ethylacetate-hexane to give the title compound (152 mg, 83%).

mp 194-195° C. IR ν max^(KBr)cm⁻¹: 1638, 1605, 1539, 1501. Anal. Calcdfor C₂₇H₂₁F₄NO₂: C, 69.37; H, 4.53; N, 3.00. Found: C, 69.32; H, 4.54;N, 2.94. ¹H-NMR (CDCl₃)δ: 2.80-3.18 (3H, m), 4.76-4.92 (1H, m), 5.98(1H, brs), 6.40 (1H, d, J=8.4 Hz), 7.00-7.14 (4H, m), 7.38 (2H, d, J=8.4Hz), 7.46-7.70 (5H, m), 7.80-7.96 (3H, m), 8.38 (1H, d, J=8.4 Hz).

Example 189

N-((1RS,2SR)-2-hydroxy-2-(1-naphthalenyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-(trifluoromethyl)benzamide

To a solution of(1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) were added4-trifluoromethylbenzoyl chloride (87.5 ml, 0.59 mmol) and saturatedaqueous sodium hydrogen carbonate (5 ml) and the mixture was stirredovernight at room temperature. The reaction solution was diluted withwater (50 ml) and extracted with ethyl acetate (50 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. The residue was recrystallizedfrom ethyl acetate-hexane to give the title compound (178 mg, 88%).

mp 232-233° C. IR ν max^(KBr)cm⁻¹: 1644, 1534. Anal. Calcd forC₂₈H₂₁F₆NO₂: C, 64.99; H, 4.09; N, 2.71. Found: C, 64.77; H, 3.93; N,2.55. ¹H-NMR (CDCl₃)δ: 2.68-2.74 (1H, m), 2.80-3.20 (2H, m), 4.82-5.00(1H, m), 6.00 (1H, s), 6.39 (1H, d, J=8.4 Hz), 7.12 (2H, d, J=8.4 Hz),7.40 (2H, d, J=8.4 Hz), 7.50-7.78 (7H, m), 7.82-7.98 (3H, m), 8.39 (1H,d, J=8.0 Hz).

Example 190N-((1RS,2SR)-2-hydroxy-2-(1-naphthalenyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)cyclohexanecarboxamide

To a solution of(1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) were addedcyclohexanecarbonyl chloride (87.8 ml, 0.59 mmol) and saturated-aqueoussodium hydrogen carbonate (5 ml) and the mixture was stirred overnightat room temperature. The reaction solution was diluted with water (50ml) and extracted with ethyl acetate (50 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1) and recrystallizedfrom ethyl acetate-hexane to give the title compound (141 mg, 79%).

mp156-157° C. IR ν max^(KBr)cm⁻¹: 1645, 1508. Anal. Calcd forC₂₇H₂₈F₃NO₂: C, 71.19; H, 6.20; N, 3.07. Found: C, 71.14; H, 6.43; N,3.06. ¹H-NMR (CDCl₃)δ: 1.00-1.44 (5H, m), 1.50-1.80 (5H, m), 1.86-2.10(1H, m), 2.70-3.10 (2H, m), 3.15 (1H, d, J=3.0 Hz), 4.52-4.70 (1H, m),5.74 (1H, d, J=8.0 Hz), 5.84 (1H, s), 7.05 (2H, d, J=8.2 Hz), 7.39 (2H,d, J=8.2 Hz), 7.44-7.70 (3H, m), 7.78-7.98 (3H, m), 8.29 (1H, d, J=8.4Hz).

Example 191N-((1RS,2SR)-2-hydroxy-2-(1-naphthalenyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-(2-thienyl)butyramide

To a solution of 4-(2-thienyl)butyric acid (86 ml, 0.59 mmol) intetrahydrofuran (5 ml) were added oxalyl chloride (0.10 ml, 1.18 mmol)and N,N-dimethylformamide (0.01 ml) and the mixture was stirred at roomtemperature for 30 min. The reaction solution was evaporated underreduced pressure. To a solution of the residue in ethyl acetate (5 ml)was added(1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylaminehydrochloride (150 mg, 0.39 mmol) and saturated aqueous sodium hydrogencarbonate (5 ml) and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (50 ml) andextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was recrystallized from ethylacetate-hexane to give the title compound (110. mg, 56%).

mp 139-140° C. IR ν max^(KBr)cm⁻¹: 1651, 1644, 1514. Anal. Calcd forC₂₈H₂₆F₃NO₂S.0.1H₂O: C, 67.34; H, 5.29; N, 2.80. Found: C, 67.18; H,5.44; N, 2.69. ¹H-NMR (CDCl₃)δ: 1.80-2.00 (2H, m), 2.02-2.30 (2H, m),2.60-3.04 (5H, m), 4.58-4.76 (1H, m), 5.75 (1H, d, J=8.4 Hz), 5.85 (1H,S), 6.64-6.70 (1H, m), 6.86-6.96 (1H, m), 7.00-7.18 (3H, m), 7.36-7.70(5H, m), 7.76-7.96 (3H, m), 8.30 (1H, d, J=8.4 Hz)

Example 192

4-fluoro-N-((1RS,2SR)-2-hydroxy-2-(4-methoxyphenyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

1) To a solution of 4-methoxybenzoic acid (26.2 g, 172 mmol) intetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole (30.7g, 189 mmol) and the mixture was stirred at room temperature for 5 hrs.To the reaction solution was added monoethyl-malonate magnesium salt(27.1 g, 94.7 mmol) was added and the mixture was stirred at 60° C. for2 hrs. Ethyl acetate (50 ml) and water (50 ml) were added to thereaction solution, and conc. hydrochloric acid was added until theaqueous layer showed acidic pH. The reaction solution was extracted withethyl acetate (200 ml×2). The extract was washed with saturated brine,dried over anhydrous magnesium sulfate and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1) to give ethyl3-(4-methoxyphenyl)-3-oxopropionate (37.6 g, 94% w/w,. 92%) as acolorless oil.

IR ν max^(KBr)cm⁻¹: 1738, 1682, 1601, 1576. Anal. Calcd for C₁₂H₁₄O₄: C,64.85; H, 6.35. Found: C, 64.93; H, 6.26. ¹H-NMR (CDCl₃)δ: 1.26 (3H, t,J=7.0 Hz), 3.85 (3/10H, s), 3.88 (27/10H, s), 3.94 (18/10H, s), 4.21(2H, q, J=7.0 Hz), 5.58 (1/10H, s), 6.90-7.00 (2H, m), 7.70-7.78 (2/10H,m), 7.88-7.98 (18/10H, m).

2) To a solution of ethyl 3-(4-methoxyphenyl)-3-oxopropionate (20 g,84.6 mmol) in acetonitrile (200 ml) were added 4-trifluoromethylbenzylbromide (20.2 g, 84.6 mmol) and potassium carbonate (23.4 g, 169 mmol)and the mixture was stirred at 60° C. for 2 hrs. The reaction solutionwas evaporated under reduced pressure, diluted with water (500 ml) andextracted with ethyl acetate (500 ml×2). The extract was washed withwater and saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (toluene:hexane=1:1-toluene) to give ethyl3-(4-methoxyphenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate(19.2 g, 56%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1732, 1682, 1601, 1576. Anal. Calcd for C₂₀H₁₉F₃O₄:C, 63.15; H, 5.03. Found: C, 63.14; H, 4.83. ¹H-NMR (CDCl₃)δ: 1.12 (3H,t, J=7.4 Hz), 3.37 (2H, d, J=7.2 Hz), 3.85 (3H, s), 4.10 (2H, q, J=7.4Hz), 4.58 (1H, t, J=7.2 Hz), 6.92 (2H, d, J=8.8 Hz), 7.35 (2H, d, J=8.0Hz), 7.51 (2H, d, J=8.0 Hz), 7.95 (2H, d, J=8.8 Hz).

3) To a solution of zinc chloride (12.3 g, 90.4 mmol) in diethyl ether(150 ml) was added sodium borohydride (6.85 g, 181 mmol) and the mixturewas stirred at room temperature for 30 min. The insoluble material wasfiltered off. To the filtrate was added a solution of ethyl3-(4-methoxyphenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate(17.2 g, 45.2 mmol) in diethyl ether (50 ml) and the mixture was stirredat room temperature for 30 min. 1N Hydrochloric acid was added to thereaction solution under ice-cooling for quenching, water (200 ml) wasadded, and the mixture was extracted with ethyl acetate (300 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethylacetate=4:1-2:1) to give ethyl(2RS,3RS)-3-hydroxy-3-(4-methoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate(15.1 g, 87%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1728, 1615, 1586, 1514. Anal. Calcd for C₂₀H₂₁F₃O₄:C, 62.82; H, 5.54. Found: C, 62.71; H, 5.42. ¹H-NMR (CDCl₃)δ: 0.91 (3H,t, J=7.0 Hz), 2.72 (1H, d, J=2.6 Hz), 2.90-3.10 (3H, m), 3.81 (3H, s),3.87 (2H, q, J=7.0 Hz), 4.96-5.04 (1H, m), 6.89 (2H, d, J=8.8 Hz), 7.22(2H, d, J=8.0 Hz), 7.31 (2H, d, J=8.8 Hz), 7.48 (2H, d, J=8.0 Hz)

4) To a solution of ethyl(2RS,3RS)-3-hydroxy-3-(4-methoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate(14.7 g, 38.4 mmol) in methanol (60 ml) was added 2N aqueous sodiumhydroxide solution (38.5 ml, 77 mmol) and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to give(2RS,3RS)-3-hydroxy-3-(4-methoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (11.7 g, 86%).

mp 113-114° C. IR ν max^(KBr)cm⁻¹: 1715, 1614, 1514. Anal. Calcd forC₁₈H₁₇F₃O₄: C, 61.02; H, 4.84. Found: C, 61.03; H, 4.85. ¹H-NMR(CDCl₃)δ: 3.03 (3H, s), 3.80 (3H, s), 4.98-5.06 (1H, m), 6.89 (2H, d,J=8.8 Hz), 7.19 (2H, d, J=8.0 Hz), 7.29 (2H, d, J=8.8 Hz), 7.47 (2H, d,J=8.0 Hz).

5) To a solution of(2RS,3RS)-3-hydroxy-3-(4-methoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (10.0 g, 28.2 mmol) in tetrahydrofuran (250 ml) were addeddiphenylphosphoryl azide (6.7 ml, 31.1 mmol) and triethylamine (5.9 ml,42.3 mmol) and the mixture was heated under reflux for 4 hrs. Thereaction solution was allowed to stand at room temperature, water (200ml) was added, and the mixture was extracted with ethyl acetate (200ml×2). The extract was washed successively with 1N hydrochloric acid,saturated aqueous sodium hydrogen carbonate and saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was recrystallized from ethyl acetate-hexane to give(4RS,5SR)-5-(4-methoxyphenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(9.89 g, 99%).

mp 164-165° C. IR ν max^(KBr)cm⁻¹: 1755, 1615, 1516. Anal. Calcd forC₁₈H₁₆F₃NO₃: C, 61.54; H, 4.59; N, 3.99. Found: C, 61.25; H, 4.50; N,3.82. ¹H-NMR (CDCl₃)δ: 2.37 (2H, d, J=7.4 Hz), 3.83 (3H, s), 4.23 (1H,q, J=7.8 Hz), 5.32 (1H, brs), 5.75 (1H, d, J=7.8 Hz), 6.88-7.00 (2H, m),7.11 (2H, d, J=8.0 Hz), 7.20-7.32 (2H, m), 7.52 (2H, d, J=8.0 Hz).

6) To a solution of(4RS,5SR)-5-(4-methoxyphenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(7.0 g, 19.9 mmol) in ethanol (100 ml) was added 8N aqueous sodiumhydroxide solution (12.45 ml, 99.6 mmol) and the mixture was heatedunder reflux for 4 hrs. The reaction solution was concentrated, dilutedwith water (300 ml) and extracted with ethyl acetate (300 ml×2). Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to give(1RS,2SR)-2-amino-1-(4-methoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(5.87 g, 91%).

mp 116-117° C. IR ν max^(KBr)cm⁻¹: 1614, 1584, 1514. Anal. Calcd forC₁₇H₁₈F₃NO₂: C, 62.76; H, 5.58; N, 4.31. Found: C, 62.74; H, 5.58; N,4.23. ¹H-NMR (CDCl₃)δ: 1.40-1.80 (2H, br), 2.45 (1H, dd, J=13.6, 10.0Hz), 2.95 (1H, dd, J=13.6, 3.2 Hz), 3.18-3.34 (1H, m), 3.82 (3H, s),4.58 (1H, d, J=5.0 Hz), 6.92 (2H, d, J=8.8 Hz), 7.22-7.38 (4H, m), 7.54(2H, d, J=8.4 Hz).

7) To a solution of(1RS,2SR)-2-amino-1-(4-methoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.38 mmol) in acetonitrile (20 ml) was added4-fluoronaphthalenecarboxylic acid (263 mg, 1.38 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (397 mg,2.08 mmol) and 1-hydroxy-1H-benzotriazole (212 mg, 1.38 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to give the titlecompound (558 mg, 81%).

mp 184-185° C. IR ν max^(KBr)cm⁻¹: 1643, 1626, 1601. Anal. Calcd forC₂₈H₂₃F₄NO₃: C, 67.60; H, 4.66; N, 2.82. Found: C, 67.37; H, 4.49; N,2.87. ¹H-NMR (CDCl₃)δ: 2.83 (1H, dd, J=14.4, 10.6 Hz), 3.07 (1H, dd,J=14.4, 4.0 Hz), 3.81 (3H, s), 4.70-4.90 (1H, m), 4.99 (1H, d, J=3.6Hz), 6.05 (1H, d, J=8.8 Hz), 6.88-7.00 (3H, m), 7.04-7.16 (1H, m),7.24-7.44 (5H, m), 7.44-7.60 (4H, m), 8.05 (1H, d, J=8.0 Hz).

Example 193N-((1RS,2SR)-2-hydroxy-2-(4-methoxyphenyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-3-phenylpropanamide

To a solution of(1RS,2SR)-2-amino-1-(4-methoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.38 mmol) in ethyl acetate (20 ml) were added3-phenylpropionyl chloride (308 ml, 2.07 mmol) and saturated aqueoussodium hydrogen carbonate (20 ml) and the mixture was stirred overnightat room temperature. The reaction solution was diluted with water (100ml) and extracted with ethyl acetate (100 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the title-compound (574 mg, 91%).

mp 116-117° C. IR ν max^(KBr)cm⁻¹: 1645, 1615. Anal. Calcd forC₂₆H₂₆F₃NO₃: C, 68.26; H, 5.73; N, 3.06. Found: C, 68.10; H, 5.99; N,2.99. ¹H-NMR (CDCl₃)δ: 2.37 (2H, t, J=7.2 Hz), 2.60-2.90 (4H, m),3.04-3.20 (1H, m), 3.81 (3H, s), 4.32-4.50 (1H, m), 4.72-4.84 (1H, m),5.35 (1H, d, J=8.4 Hz), 6.88 (2H, d, J=8.8 Hz), 7.08-7.40 (9H, m), 7.46(2H, d, J=8.0 Hz).

Example 194N-[(1RS,2SR)-2-(4-chlorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-4-fluoronaphthalene-1-carboxamide

1) ethyl (4-chlorobenzoyl)acetate

To a solution of 4-chlorobenzoic acid (15.77 g, 100.7 mmol) intetrahydrofuran (100 ml) was added 1,1′-carbonyldiimidazole (18.0 g, 111mmol) at room temperature and the mixture was stirred as it was for 6hrs. To the mixture was added monoethyl malonate monomagnesium salt(15.9 g, 55.4 mmol) at room temperature and the mixture was stirred at60° C. for 3 hrs. The reaction solution was diluted with ethyl acetateand water and acidified with conc. hydrochloric acid. The ethyl acetatelayer was separated and the aqueous layer was extracted with ethylacetate. The collected organic layer was dried over anhydrous sodiumsulfate and the solvent was evaporated under reduced pressure. Theobtained crude product was purified by silica gel column chromatography(hexane/ethyl acetate=6/1) to give the objective substance.

red liquid yield 19.64 g, 86% ¹H-NMR (CDCl₃, 200 MHz) δ 1.26 (2.4H, t,J=7.4 Hz), 1.34 (0.6H, t, J=7.0 Hz), 3.97 (1.6H, s), 4.22 (1.6H, q,J=7.1 Hz), 4.27 (0.4H, q, J=7.1 Hz), 5.64 (0.2H, s), 7.40 (0.4H, d,J=8.8 Hz), 7.46 (1.6H, d, J=8.6 Hz), 7.72 (0.4H, d, J=8.6 Hz), 7.90(1.6H, d, J=8.0 Hz); IR (neat) 1742, 1690, 1622, 1590, 1325, 1265, 1200,1092, 1013 cm⁻¹

2) ethyl3-(4-chlorophenyl)-3-oxo-2-[4-(trifluoromethyl)benzyl]propionate

To a solution of ethyl (4-chlorobenzoyl)acetate (14.28 g, 63.00 mmol) in1,2-dimethoxyethane (100 ml) was added a suspension (2.52 g, 63.0 mmol)of 60% sodium hydride in liquid paraffin under ice-cooling and themixture was stirred as it was for 0.5 hr. A solution of4-(trifluoromethyl)benzyl bromide (15.1 g, 63.0 mmol) in1,2-dimethoxyethane (20 ml) was added at room temperature and themixture was stirred at room temperature for 6 hrs. The reaction solutionwas-poured into water and extracted twice with ethyl acetate. Thecollected organic layer was dried over anhydrous magnesium sulfate andthe solvent was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (hexane/ethylacetate=15/1-9/1) and crystallized from hexane to give the objectivesubstance.

white crystal yield 18.87 g, 78% mp 69-70° C.; ¹H-NMR (CDCl₃, 200 MHz) δ1.12 (3H, t, J=7.1 Hz), 3.38 (2H, d, J=7.4 Hz), 4.10 (2H, q, J=7.3 Hz),4.56 (1H, t, J=7.5 Hz), 7.34 (2H, d, J=8.0 Hz), 7.43 (2H, d, J=8.8 Hz),7.52 (2H, d, J=8.0 Hz), 7.90 (2H, d, J=8.4 Hz); IR (KBr) 1717, 1690,1590, 1329, 1283, 1229, 1179, 1157, 1111, 1092, 1071, 845, 828 cm⁻¹;Anal. Calcd for C₁₉H₁₆ClF₃O₃: C, 59.31; H, 4.19. Found: C, 59.29; H,4.05.

3) ethyl(2RS,3RS)-3-(4-chlorophenyl)-3-hydroxy-2-[4-(trifluoromethyl)benzyl]propionate

While stirring zinc chloride (7.18 g, 52.7 mmol) in diethyl ether (100ml), sodium borohydride (3.98 g, 105 mmol) was added at room temperatureand the mixture was stirred as it was for 2 hrs. The insoluble materialof the mixture was removed by filtration and washed with diethyl etherto give a solution of zinc borohydride in diethyl ether. To the obtainedsolution was added a solution of ethyl3-(4-chlorophenyl)-3-oxo-2-[4-(trifluoromethyl)benzyl]propionate (10.13g, 26.33 mmol) in diethyl ether (50 ml) at room temperature and themixture was stirred as it was for 2 hrs. Dilute hydrochloric acid wasadded to the reaction solution by small portions to decompose excesszinc borohydride and extracted twice with ethyl acetate. The collectedorganic layer was dried over anhydrous magnesium sulfate and the solventwas evaporated under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (hexane/ethylacetate=9/1-3/1) to give the objective substance.

colorless liquid yield 9.971 g, 98% ¹H-NMR (CDCl₃, 200 MHz) δ 0.93 (3H,t, J=7.1 Hz), 2.90-3.14 (4H, m), 3.90 (2H, q, J=7.1 Hz), 5.04 (1H, dd,J=3.0 Hz, 4.8 Hz), 7.19 (2H, d, J=8.2 Hz), 7.34 (4H, s), 7.48 (2H, d,J=8.2 Hz); IR (neat) 3466, 1715, 1325, 1163, 1125, 1109, 1069, 1019, 829cm⁻¹

4)(2RS,3RS)-3-(4-chlorophenyl)-3-hydroxy-2-[4-(trifluoromethyl)benzyl]propionicacid

To a solution of ethyl(2RS,3RS)-3-(4-chlorophenyl)-3-hydroxy-2-[4-(trifluoromethyl)benzyl]propionate(9.756 g, 25.22 mmol) in methanol (40 ml) and tetrahydrofuran (40 ml)was added 1N aqueous sodium hydroxide solution (50.4 ml, 50.4 mmol) andthe mixture was stirred overnight at room temperature. The reactionsolution was concentrated, diluted with water, acidified with 1Nhydrochloric acid and extracted twice with ethyl acetate. The collectedorganic layer was dried over anhydrous sodium sulfate and the solventwas evaporated under reduced pressure. The residue was crystallized fromdiethyl ether-hexane to give the objective substance.

white crystal yield. 7.152 g, 79% mp 100-101° C.; ¹H-NMR (CDCl₃200 MHz)δ 2.94-3.13 (3H, m), 5.09 (1H, t, J=2.2 Hz), 7.18 (2H, d, J=7.6 Hz),7.34 (4H, s), 7.48 (2H, d, J=8.0 Hz); IR (KBr) 3400-2550, 1696, 1323,1167, 1130, 1119, 1107, 828 cm⁻¹; Anal. Calcd for C₁₇H₁₄ClF₃O₃: C,56.92; H, 3.93. Found: C, 56.98; H, 3.73.

5)(4RS,5SR)-5-(4-chlorophenyl)-4-[4-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-(4-chlorophenyl)-3-hydroxy-2-[4-(trifluoromethyl)benzyl]propionicacid (6.931 g, 19.32 mmol) in tetrahydrofuran (80 ml) were addedtriethylamine (4.04 ml, 29.0 mmol) and diphenylphosphoryl azide (5.85 g,21.3 mmol) and the mixture was heated under reflux overnight. Thesolvent of the reaction solution was evaporated under reduced pressure,the obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1) and crystallized fromethyl acetate-hexane to give the objective substance.

white crystal yield 6.120 g, 89% mp 159-160° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.24-2.40 (2H, m), 4.20-4.32 (1H, m), 5.02 (1H, br s), 5.80 (1H, d,J=8.2 Hz), 7.15 (2H, d, J=8.0 Hz), 7.32 (2H, d, J=8.4 Hz), 7.42 (2H, d,J=8.4 Hz), 7.55 (2H, d, J=8.0 Hz); IR (KBr) 3248, 1736, 1327, 1167,1138, 1109, 1096, 1067 cm⁻¹; Anal. Calcd for C₁₇H₁₃ClF₃NO₂: C, 57.40; H,3.68; N, 3.94. Found: C, 57.41; H, 3.58; N, 3.85.

6)(1RS,2SR)-2-amino-1-(4-chlorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol

(4RS,5SR)-5-(4-Chlorophenyl)-4-[4-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one(5.902 g, 16.59 mmol) and sodium hydroxide (2.65 g, 66.4 mmol) wereheated under reflux in ethanol (40 ml) and water (2.5 ml) for 7 hrs. Thereaction solution was diluted with water and stirred as it was for 10min. The resulting precipitate was collected by filtration and washedwith water to give the objective substance.

white crystal yield 4.902 g, 90% mp 103-105° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.41 (1H, dd, J=10.3 Hz, 13.5 Hz.), 2.83 (1H, dd, J=3.1 Hz, 13.7 Hz),3.29 (1H, ddd, J=3.3 Hz, 4.9 Hz, 10.5 Hz), 4.66 (1H, d, J=4.8 Hz), 7.25(2H, d, J=8.0 Hz), 7.31-7.40 (4H, m), 7.54 (2H, d, J=8.0 Hz); IR (KBr)3150-2760, 1329, 1165, 1130, 1115, 1069, 1042, 851 cm⁻¹; Anal. Calcd forC₁₆H₁₅ClF₃NO: C, 58.28; H, 4.59; N, 4.25. Found: C, 58.03; H, 4.72; N,4.16.

7)N-[(1RS,2SR)-2-(4-chlorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-4-fluoronaphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-chlorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.173 g, 0.525 mmol), 4-fluoro-1-naphthoate (0.10 g, 0.52 mmol) and1-hydroxybenzotriazole hydrate (80 mg, 0.52 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10g, 0.52 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from ethyl acetate-hexane to give the objective substance.

white crystal yield 0.216 g, 82% mp 203-204° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.93 (1H, dd, J=10.6 Hz, 14.4 Hz), 3.11 (1H, dd, J=3.1 Hz,13.3 Hz), 4.66-4.81 (1H, m), 4.95 (1H, t, J=4.6 Hz), 5.43 (1H, d, J=4.0Hz), 7.05 (1H, dd, J=7.7 Hz, 9.9 Hz), 7.20 (1H, dd, J=5.5 Hz, 8.1 Hz),7.33-7.57 (11H, m), 7.71 (1H, d, J=9.6 Hz), 8.05 (1H, d, J=8.4 Hz); IR(KBr) 3343, 1638, 1620, 1601, 1534, 1327, 1159, 1125, 1069, 833 cm⁻¹;Anal. Calcd for C₂₇H₂₀ClF₄NO₂: C, 64.61; H, 4.02; N, 2.79. Found: C,64.42; H, 3.98; N, 2.61.

Example 1954-fluoro-N-((1RS,2SR)-2-(3-furanyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

1) To a solution of 3-furancarboxylic acid (25.5 g, 227 mmol) intetrahydrofuran (200 ml) was added 1,1′-carbonylbis-1H-imidazole (40.5g, 250 mmol) and the mixture was stirred at 60° C. for 2 hrs. To thereaction solution was added monoethyl malonate magnesium salt (35.8 g,125 mmol) and the mixture was heated under reflux for 30 min. Ethylacetate (50 ml) and water (50 ml) were added the reaction solution, andconc. hydrochloric acid was added until the aqueous layer showed acidicpH. The reaction solution was extracted with ethyl acetate (200 ml×2).The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=4:1)to give ethyl 3-(3-furanyl)-3-oxopropionate (42 g, 100%) as a colorlessoil.

IR ν max^(KBr)cm⁻¹: 1738, 1682. Anal. Calcd for C₉H₁₀O₄.0.1H₂O: C,58.76;,H, 5.59. Found: C, 58.90; H, 5.56. ¹H-NMR (CDCl₃)δ: 1.27 (3H, t,J=7.0 Hz), 3.78 (18/10H, s), 4.21 (2H, q, J=7.0 Hz), 5.37 (1/10H, s),6.57 (1/10H, s), 6.79 (9/10H, s), 7.40-7.50 (1H, m), 7.90 (1/10H, s),8.11 (9/10H, s).

2) To a solution of ethyl 3-(3-furanyl)-3-oxopropionate (20 g, 110 mmol)in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil,4.4 g, 110 mmol) under ice-cooling and the mixture was stirred at roomtemperature for 30 min. To the reaction solution was dropwise added asolution of 4-trifluoromethylbenzyl bromide (26.2 g, 110 mmol) in1,2-dimethoxyethane (50 ml) and the reaction solution was stirred atroom temperature for 3 hrs. The reaction solution was poured into water(300 ml) and extracted with ethyl acetate (500 ml×2). The extract waswashed with water and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue wasrecrystallized from diisopropyl ether-hexane to give ethyl3-(3-furanyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate(28.8 g, 77%).

mp 55-56° C. IR ν max^(KBr)cm⁻¹: 1738, 1682. Anal. Calcd for C₁₇H₁₅F₃O₄:C, 60.00; H, 4.44. Found: C, 59.89; H, 4.38. ¹H-NMR (CDCl₃)δ: 1.16 (3H,t, J=7.0 Hz), 3.35 (2H, d, J=7.6 Hz), 4.06-4.24 (3H, m), 6.76-6.80 (1H,m), 7.34 (2H, d, J=8.0 Hz), 7.40-7.48 (1H, m), 7.53 (2H, d, J=8.0 Hz),8.09 (1H, s).

3) To a solution of zinc chloride (16.0 g, 117 mmol) in diethyl ether(250 ml) was added sodium borohydride (8.9 g, 235 mmol) and the mixturewas stirred at room temperature for 2 hrs. The insoluble material wasfiltered off. To the filtrate was added a solution of ethyl3-(3-furanyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (20g, 58.8 mmol) in diethyl ether (50 ml) and the mixture was stirred atroom temperature for 30 min. 1N Hydrochloric acid was added to thereaction solution under ice-cooling for quenching, water (200 ml), andthe mixture was extracted with ethyl acetate (300 ml×2). The extract waswashed with water and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure to give ethyl(2RS,3RS)-3-(3-furanyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate(19.7 g, 98%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1728. Anal. Calcd for C₁₇H₁₇F₃O₄: C, 59.65; H, 5.01.Found: C, 59.35; H, 5.19. ¹H-NMR (CDCl₃)δ: 1.00 (3H, t, J=7.2 Hz), 2.80(1H, d, J=3.8 Hz), 2.86-3.14 (3H, m), 3.96 (2H, q, J=7.2 Hz), 5.01 (1H,t, J=4.0 Hz), 6.40 (1H, s), 7.25 (2H, d, J=8.0 Hz), 7.38-7.60 (4H, m).

4) To a solution of ethyl(2RS,3RS)-3-(3-furanyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate(19.0 g, 55.5 mmol) in methanol (100 ml) was added 2N aqueous sodiumhydroxide solution (55.5 ml, 111 mmol) and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from diisopropyl ether-hexane to give(2RS,3RS)-3-(3-furanyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (15.1 g, 86%).

mp 104-105° C. IR ν max^(KBr)cm⁻¹: 1713. Anal. Calcd for C₁₅H₁₃F₃O₄: C,57.33; H, 4.17. Found: C, 57.42; H, 4.15. ¹H-NMR (CDCl₃)δ: 2.90-3.20(3H, m), 5.02 (1H, d, J=4.0 Hz), 6.39 (1H, s), 7.26 (2H, d, J=8.2 Hz),7.40-7.50 (2H, m), 7.52 (2H, d, J=8.2 Hz).

5) To a solution of(2RS,3RS)-3-(3-furanyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (10.0 g, 31.8 mmol) in tetrahydrofuran (250 ml) were addeddiphenylphosphoryl azide (7.5 ml, 35.0 mmol) and triethylamine (6.7 ml,47.7 mmol) and the mixture was heated under reflux for 4 hrs. Thereaction solution was allowed to stand at room temperature, water (200ml) was added, and the mixture was extracted with ethyl acetate (200ml×2). The extract was washed successively with 1N hydrochloric acid,saturated aqueous-sodium hydrogen carbonate and saturated brine, dried,over anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was recrystallized from diisopropyl ether-hexane to give(4RS,5SR)-5-(3-furanyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(8.25 g, 83%)

mp 111-112° C. IR ν max^(KBr)cm⁻¹: 1759. Anal. Calcd for C₁₅H₁₂F₃NO₃: C,57.88; H, 3.89; N, 4.50. Found: C, 57.94; H, 3.97; N, 4.38. ¹H-NMR(CDCl₃)δ: 2.48-2.72 (2H, m), 4.12-4.28 (1H, m), 5.09 (1H, brs), 5.75(1H, d, J=7.8 Hz), 6.47 (1H, s), 7.22 (2H, d, J=8.0 Hz), 7.48-7.62 (4H,m).

6) To a solution of(4RS,5SR)-5-(3-furanyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(7.0 g, 22.5 mmol) in ethanol (100 ml) was added 8N aqueous sodiumhydroxide solution (14.0 ml, 112.5 mmol) and the mixture was heatedunder reflux for 3 hrs. The reaction solution was concentrated, dilutedwith water (300 ml) and extracted with ethyl acetate (300 ml×2). Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to give(1RS,2SR)-2-amino-1-(3-furanyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(5.54 g, 86%).

mp 91-92° C. IR ν max^(KBr)cm⁻¹: 1572, 1500, 1331. Anal. Calcd forC₁₄H₁₄F₃NO₂: C, 58.95; H, 4.95; N, 4.91. Found: C, 58.91; H, 5.08; N,4.78. ¹H-NMR (CDCl₃)δ: 2.49 (1H, dd, J=13.6, 9.8 Hz), 2.96 (1H, dd,J=14.0, 3.6 Hz), 3.20-3.32 (1H, m), 4.62 (1H, d, J=5.2 Hz), 6.44 (1H,s), 7.30 (2H, d, J=8.0 Hz), 7.40-7.50 (2H, m), 7.56 (2H, d, J=8.0 Hz).

7) To a solution of(1RS,2SR)-2-amino-1-(3-furanyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(500 mg, 1.75 mmol) in acetonitrile (30 ml) were added4-fluoronaphthalenecarboxylic acid (333 mg, 1.75 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (504 mg,2.63 mmol) and 1-hydroxy-1H-benzotriazole (268 mg, 1.75 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1). Recrystallization from ethyl acetate-hexane gave the titlecompound (573 mg, 71%).

mp 206-207° C. IR ν max^(KBr)cm⁻¹: 1644, 1626, 1601, 1537, 1329. Anal.Calcd for C₂₅H₁₉F₄NO₃: C, 65.64; H, 4.19; N., 3.06. Found: C, 65.49; H,4.37; N, 2.91. ¹H-NMR (CDCl₃)δ: 2.89 (1H, dd, J=14.2, 10.2 Hz), 3.15(1H, dd, J=14.2, 4.2 Hz), 3.24 (1H, brs), 4.70-4.88 (1H, m), 5.03 (1H,d, J=3.2 Hz), 6.02 (1H, d, J=8.6 Hz), 6.51 (1H, s), 6.92-7.08 (1H, m),7.12-7.24 (1H, m), 7.30-7.62 (8H, m), 7.70 (1H, d, J=8.4 Hz), 8.08 (1H,d, J=8.2 Hz).

Example 196N-((1RS,2SR)-2-(3-furanyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-3-phenylpropanamide

To a solution of(1RS,2SR)-2-amino-1-(3-furanyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(500 mg, 1.75 mmol) in ethyl acetate (20 ml) were added3-phenylpropionyl chloride (390 ml, 2.63 mmol) and saturated aqueoussodium hydrogen carbonate (20 ml) and the mixture was stirredovernight-at room temperature. The reaction solution was diluted withwater (100 ml) and extracted with ethyl acetate (100 ml×2). The extractwas washed with saturated-brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. The residue was recrystallizedfrom ethyl acetate-hexane to give the title compound (650 mg, 89%).

mp 134-135° C. IR ν max^(KBr)cm⁻¹: 1645, 1520. Anal. Calcd forC₂₃H₂₂F₃NO₃: C, 66.18; H, 5.31; N, 3.36. Found: C, 66.18; H, 5.40; N,3.22. ¹H-NMR (CDCl₃)δ: 2.39 (2H, t, J=7.0 Hz), 2.64-2.92 (4H, m),3.08-3.36 (1H, m), 4.26-4.44 (1H, m), 4.75 (1H, s), 5.30-5.50 (1H, m),6.31 (1H, s), 7.06-7.34 (7H, m), 7.38 (2H, d, J=6.8 Hz), 7.49 (2H, d,J=8.2 Hz).

Example 197 N-[(1RS,2RS)-2-(5-chloro-2-thienyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-4-fluoronaphthalene-1-carboxamide

1) ethyl 3-(5-chloro-2-thienyl)-3-oxopropionate

To a solution of 5-chlorothiophene-2-carboxylic acid (10.12 g, 62.24mmol) in tetrahydrofuran (80 ml) was added 1,1′-carbonyldiimidazole(11.1 g, 68.5 mmol) at room temperature and the mixture was stirred asit was for 6 hrs. Monoethyl malonate monomagnesium salt (9.81 g, 34.2mmol) was added to this mixture at room temperature and the mixture wasstirred at 60° C. for 3 hrs. The reaction solution was diluted withethyl acetate and water, and acidified with conc. hydrochloric acid. Theethyl acetate layer was separated, and the aqueous layer was extractedwith ethyl acetate. The collected organic layer was dried over anhydroussodium sulfate and the solvent was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=6/1) to give the objectivesubstance.

dark red liquid yield 13.89 g, 96% ¹H-NMR (CDCl₃, 200 MHz) δ 1.27 (3H,t, J=7.2 Hz), 3.85 (2H, s), 4.21 (2H, q, J=7.1 Hz), 6.99 (1H, d, J=4.0Hz), 7.53 (1H, d, J=4.0 Hz); IR (neat) 1738, 1667, 1418, 1329, 1215,1017 cm⁻¹

2) ethyl3-(5-chloro-2-thienyl)-3-oxo-2-[4-(trifluoromethyl)benzyl]propionate

To a solution of ethyl 3-(5-chloro-2-thienyl)-3-oxopropionate (13.57 g,58.32 mmol) in 1,2-dimethoxyethane (100 ml) was added a suspension (2.33g, 58.3 mmol) of 60% sodium hydride in liquid paraffin underice-cooling, and the mixture was stirred as it was for 0.5 hr. Asolution of 4-(trifluoromethyl)benzyl bromide (13.9 g, 58.3 mmol) in1,2-dimethoxyethane (20 ml) was added at room temperature, and themixture was stirred at room temperature was for 6 hrs. The reactionsolution was poured into water, and extracted twice with ethyl acetate.The collected organic layer was dried over anhydrous magnesium sulfateand the solvent was evaporated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane/ethylacetate=15/1-9/1) and crystallized from hexane to give the objectivesubstance.

white crystal yield 18.30 g, 80% mp 87-88° C.; ¹H-NMR (CDCl₃, 200 MHz) δ1.16 (3H, t, J=7.2 Hz), 3.36 (2H, d, J=7.8 Hz), 4.14 (2H, q, J=7.2 Hz),4.35 (1H, t, J=7.5 Hz), 6.94 (1H, d, J=4.0 Hz), 7.33 (2H, d, J=8.0 z),7.53 (2H, d, J=8.4 Hz), 7.55 (1H, d, J=4.0 Hz); IR (KBr) 1721, 1659,1418, 1329, 1285, 1236, 1155, 1119, 1071 cm⁻¹; Anal. Calcd forC₁₇H₁₄ClF₃O₃S: C, 52.25; H, 3.61. Found: C, 52.22; H, 3.42.

3) ethyl(2RS,3RS)-3-(5-chloro-2-thienyl)-3-hydroxy-2-[4-(trifluoromethyl)benzyl]propionate

While stirring zinc chloride (6.47 g, 47.5 mmol) in diethyl ether (100ml), sodium borohydride (3.59 g, 94.9 mmol) was added at roomtemperature, and the mixture was-stirred as it was for 2 hrs. Theinsoluble material of the mixture was removed by filtration (washed withdiethyl ether) to give a solution of zinc borohydride in diethyl ether.To the obtained solution was added a solution of ethyl3-(5-chloro-2-thienyl)-3-oxo-2-[4-(trifluoromethyl)benzyl]propionate(9.272 g, 23.73 mmol) in diethyl ether (50 ml) at room temperature, andthe mixture was stirred as it was for 2 hrs. Dilute hydrochloric acidwas added to the reaction solution by small portions to decompose excesszinc borohydride. The mixture was extracted twice with ethyl acetate.The collected organic layer was dried over anhydrous magnesium sulfateand the solvent was evaporated under reduced pressure. The obtainedcrude product was purified by silica gel column chromatography(hexane/ethyl acetate=9/1-3/1) to give the objective substance.

colorless liquid yield 9.093 g, 98% ¹H-NMR (CDCl₃, 200 MHz) δ 0.99 (3H,t, J=7.1 Hz), 2.96-3.16 (4H, m), 3.96 (2H, q, J=7.1 Hz), 5.15 (1H, t,J=4.2 Hz), 6.76 (1H, d, J=3.8 Hz), 6.79 (1H, d, J=3.6 Hz), 7.26 (2H, d,J=8.2 Hz), 7.52 (2H, d, J=8.0 Hz); IR (neat) 3459, 1715, 1325, 1163,1125, 1109, 1069, 1020 cm⁻¹

4)(2RS,3RS)-3-(5-chloro-2-thienyl)-3-hydroxy-2-[4-(trifluoromethyl)benzyl]propionicacid

To a solution of ethyl(2RS,3RS)-3-(5-chloro-2-thienyl)-3-hydroxy-2-[4-(trifluoromethyl)benzyl]propionate(8.878 g, 22.60 mmol) in methanol (30 ml)-tetrahydrofuran (30 ml) wasadded 1N aqueous sodium hydroxide solution (45.2 ml, 45.2 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas concentrated, diluted with water, acidified with 1N hydrochloricacid, and extracted twice with ethyl acetate. The collected-organiclayer was dried over anhydrous sodium sulfate and the solvent wasevaporated under reduced pressure. The residue was crystallized fromdiethyl ether-hexane to give the objective substance.

white crystal yield 7.092 g, 86% mp 150-151° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 3.06-3.15 (3H, m), 5.17 (1H, d, J=4.8 Hz), 6.79 (2H, s), 7.27 (2H, d,J=8.0 Hz), 7.53 (2H, d, J=8.4 Hz); IR (KBr) 3382, 3050-2650, 1698, 1333,1159, 1130, 1111, 1071, 802 cm⁻¹; Anal. Calcd for C₁₅H₁₂ClF₃O₃S: C,49.39; H, 3.32. Found: C, 49.40; H, 3.29.

5)(4RS,5RS)-5-(5-chloro-2-thienyl)-4-[4-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-(5-chloro-2-thienyl)-3-hydroxy-2-[4-(trifluoromethyl)benzyl]propionicacid (6.918 g, 18.97 mmol) in tetrahydrofuran (80 ml) were addedtriethylamine (3.97 ml, 28.4 mmol) and diphenylphosphoryl azide (5.74 g,20.9 mmol), and the mixture was heated under reflux overnight. Thesolvent of the reaction solution was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1) and crystallized fromdiethyl ether-hexane to give the objective substance.

white crystal yield 5.985 g, 87% mp 127-128° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.54-2.75 (2H, m), 4.25 (1H, ddd, 4.7 Hz, 8.0 Hz, 10.1 Hz), 5.10 (1H,br s), 5.72 (1H, d, J=7.6 Hz), 6.89 (2H, s), 7.22 (2H, d, J=8.0 Hz),7.58 (2H, d, J=8.6 Hz); IR (KBr) 3248, 1736, 1327, 1159, 1127, 1069cm⁻¹; Anal. Calcd for C₁₅H₁₁ClF₃NO₂S: C, 49.80; H, 3.06; N, 3.87. Found:C, 49.77; H, 2.95; N, 3.65.

6)(1RS,2RS)-2-amino-1-(5-chloro-2-thienyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol

(4RS,5RS)-5-(5-Chloro-2-thienyl)-4-[4-(trifluoromethyl)-benzyl]-1,3-oxazolidin-2-one(2.951 g, 8.157 mmol) and sodium hydroxide (1.31 g, 32.6 mmol) wereheated under reflux in ethanol (30 ml)-water (1.5 ml) for 7 hrs. Thereaction solution was diluted with brine, and extracted twice with ethylacetate. The collected organic layer was dried over anhydrous sodiumsulfate and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel (APS type) column chromatography(hexane/ethyl acetate=3/1-ethyl acetate) and crystallized from ethylacetate-hexane to give the objective substance.

white crystal yield 1.318 g, 48% mp 86-87° C.; ¹H-NMR (CDCl₃, 200 MHz) δ2.49 (1H, dd, J=9.7 Hz, 13.7 Hz), 2.92 (1H, dd, J=3.9 Hz, 13.7 Hz),3.28-3.38 (1H, m), 4.77 (1H, d, J=4.8 Hz), 6.79 (1H, d, J=3.8 Hz), 6.83(1H, d, J=3.6 Hz), 7.30 (2H, d, J=8.6 Hz), 7.57 (2H, d, J=8.0 Hz); IR(KBr) 3100-2700, 1327, 1163, 1117, 1069, 1038, 802 cm⁻¹; Anal. Calcd forC₁₄H₁₃ClF₃NOS: C, 50.08; H, 3.90; N, 4.17. Found: C, 49.99; H, 3.92; N,4.11.

7)N-[(1RS,2RS)-2-(5-chloro-2-thienyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-4-fluoronaphthalene-1-carboxamide

While stirring(1RS,2RS)-2-amino-1-(5-chloro-2-thienyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.168 g, 0.500 mmol), 4-fluoro-1-naphthoic acid (0.10 g, 0.50 mmol) and1-hydroxybenzotriazole hydrate (77 mg, 0.50 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10g, 0.50 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction was diluted with ethyl acetate, washed withaqueous sodium hydrogen carbonate solution, dried over anhydrousmagnesium sulfate and passed through silica gel. Thee solvent wasevaporated under reduced pressure. The obtained residue was crystallizedfrom ethyl acetate-hexane to give the objective substance.

white crystal yield 0.186 g, 73% mp 201-203° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.95 (1H, dd, J=10.6 Hz, 14.0 Hz), 3.21 (1H, dd, J=2.8 Hz,14.6 Hz), 4.66-4.80 (1H, m), 5.10 (1H, t, J=4.7 Hz), 5.86 (1H, d, J=4.4Hz), 6.85 (1H, d, J=3.6 Hz), 6.91 (1H, d, J=4.0 Hz), 7.07 (1H, dd, J=7.9Hz, 10.1 Hz), 7.28 (1H, dd, J=5.4 Hz, 8.0 Hz), 7.39-7.64 (7H, m), 7.79(1H, d, J=9.6 Hz), 8.06 (1H, d, J=7.8 Hz); IR (KBr) 3275, 1644, 1626,1537, 1325, 1167, 1121, 1069, 760 cm⁻¹; Anal. Calcd for C₂₅H₁₈ClF₄NO₂S:C, 59.12; H, 3.57; N, 2.76. Found: C, 59.05; H; 3.47; N, 2.49.

Example 198N-[(1RS,2RS)-2-(5-chloro-2-thienyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2RS)-2-amino-1-(5-chloro-2-thienyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol(0.235 g, 0.700 mmol), 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylicacid (0.13 g, 0.70 mmol) and 1-hydroxybenzotriazole hydrate (0.11 g,0.70 mmol) in acetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.13 g, 0.70 mmol) was added, and themixture was stirred overnight at room temperature. The reaction wasdiluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate and passedthrough silica gel. The solvent was evaporated under reduced pressure.The obtained residue was crystallized from diisopropyl ether-hexane togive the objective substance.

white-crystal yield 0.298 g, 84% mp 184-185° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.94-2.06 (2H, m), 2.15-2.24 (2H, m), 2.67 (2H, t, J=5.8 Hz), 2.86(1H, dd, J=10.5 Hz, 14.5 Hz), 3.09 (1H, dd, J=4.5 Hz, 14.1 Hz), 4.25(1H, d, J=4.0 Hz), 4.63-4.76 (1H, m), 0.15 (1H, t, J=3.8 Hz), 5.83 (1H,d, J=8.8 Hz), 5.91 (1H, td, J=5.3 Hz, 11.8 Hz), 6.19 (1H, d, J=11.8 Hz),6.84 (2H, s), 7.00-7.21 (3H, m), 7.33 (2H, d, J=8.0 Hz), 7.57 (2H, d,J=8.0 Hz); IR (KBr) 3283, 1638, 1526, 1327, 1161, 1125, 1069 cm⁻¹; Anal.Calcd for C₂₆H₂₃ClF₃NO₂S: C, 61.72; H, 4.58; N, 2.77. Found: C, 61.57;H, 4.35; N, 2.71.

Example 199 1,1-dimethylethyl(1RS,2SR)-2-hydroxy-2-(4-pyridyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethylcarbamate

1) To a solution of 4-pyridinecarboxylic acid (50.0 g, 406 mmol) intetrahydrofuran (250 ml) was added 1,1′-carbonylbis-1H-imidazole (72.5g, 447 mmol), and the mixture was stirred at room temperature for 30min. To the reaction solution was added monoethyl malonate magnesiumsalt (82.9 g, 487 mmol), and the mixture was heated under reflux for 30min. To the reaction solution were added ethyl acetate (200 ml) andwater (200 ml), and citric acid was added until the pH of the aqueouslayer became 7. The reaction solution was extracted with ethyl acetate(400 ml×2). The extract was washed with saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was washed with diisopropyl ether-hexane and recrystallized fromdiisopropyl ether-hexane to give ethyl 3-oxo-3-(4-pyridyl)propionate(13.3 g, 17%).

mp 60-61° C. IR ν max^(KBr)cm⁻¹: 1744, 1699, 1651, 1634, 1595, 1553.Anal. Calcd for C₁₀H₁₁NO₃: C, 62.17; H, 5.74; N, 7.25. Found: C, 62.17;H, 5.86; N, 7.22. ¹H-NMR (CDCl₃)δ: 1.26 (3/7H, t, J=7.2 Hz), 1.35(18/7H, t, J=7.2 Hz), 4.00 (2/7H, s), 4.18-4.40 (2H, m), 5.77 (6/7H, s),7.61. (12/7H, d, J=4.8 Hz), 7.74 (2/7H, d, J=4.8 Hz), 8.71 (12/7H, d,J=4.8 Hz), 8.83 (2/7H, d, J=4.8 Hz), 12.44 (6/7H, s).

2) To a solution of ethyl 3-oxo-3-(4-pyridyl)propionate (13.9 g, 72.0mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% inoil, 2.88 g, 72.0 mmol) under ice-cooling, and the mixture was stirredat room temperature for 30 min. To the reaction solution was dropwiseadded a solution of 4-trifluoromethylbenzyl bromide (17.2 g, 72.0 mmol)in 1,2-dimethoxyethane (50 ml), and the mixture was stirred at roomtemperature for 4 hrs. The reaction solution was poured into water (300ml), and extracted with ethyl acetate (500 ml×2). The extract was washedwith water and saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate=4:1) andrecrystallized from ethyl acetate-hexane to give ethyl3-oxo-3-(4-pyridyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate(10.9 g, 43%).

mp 64-65° C. IR ν max^(KBr)cm⁻¹: 1738, 1699. Anal. Calcd forC₁₈H₁₆F₃NO₃: C, 61.54; H, 4.59; N, 3.99. Found: C, 61.61; H, 4.44; N,3.93. ¹H-NMR (CDCl₃)δ: 1.11 (3H, t, J=7.0 Hz), 3.39 (2H, d, J=7.4 Hz),4.11 (2H, q, J=7.0 Hz), 4.56 (1H, t, J=7.4 Hz), 7.35 (2H, d, J=8.0 Hz),7.54 (2H, d, J=8.0 Hz), 7.66-7.78 (2H, m), 8.76-8.88 (2H, m).

3) To a solution of zinc chloride (8.14 g, 59.8 mmol) in diethyl ether(200 ml) was added sodium borohydride (4.53 g, 120 mmol), andthe-mixture was stirred at room temperature for 30 min. The insolublematerial was filtered off, and to the filtrate was added ethyl3-oxo-3-(4-pyridyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate(10.5 g, 29.9 mmol) in diethyl ether (50 ml). The mixture was stirred atroom temperature for 30 min. and 1N hydrochloric acid was added to thereaction solution under ice-cooling to quench the reaction. Saturatedaqueous sodium hydrogen carbonate was added until the pH became 8, andthe mixture was extracted with ethyl acetate (300 ml×2). The extract waswashed with water and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate) and recrystallizedfrom diisopropyl ether-hexane to give ethyl(2RS,3RS)-3-hydroxy-3-(4-pyridyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate(9.52 g, 90%).

mp 78-80° C. IR ν max^(KBr)cm⁻¹: 1726, 1630, 1618. ¹H-NMR (CDCl₃)δ: 0.98(3H, t, J=7.4 Hz), 2.72-2.82 (1H, m), 2.90-3.20 (2H, m), 3.58 (1H, d,J=2.6 Hz), 3.97 (2H, q, J=7.4 Hz), 5.21 (1H, s), 7.16 (2H, d, J=8.0 Hz),7.40-7.70 (4H, m), 8.59 (2H, d, J=6.2 Hz).

4) To a solution of ethyl(2RS,3RS)-3-hydroxy-3-(4-pyridyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate(9.36 g, 26.5 mmol) in methanol (40 ml) was added 2N aqueous sodiumhydroxide solution (26 ml, 52 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate wasadded to adjust the pH to 6, and the mixture was extracted with ethylacetate (200 ml×2). The extract was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure to give(2RS,3RS)-3-hydroxy-3-(4-pyridyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (7.8 g, 90%).

IR ν max^(KBr)cm⁻¹: 1725. ¹H-NMR (CD₃OD)δ: 3.10-3.24 (3H, m), 5.26 (1H,d, J=4.8 Hz), 7.34 (2H, d, J=8.0 Hz), 7.49 (2H, d, J=8.0 Hz), 8.07 (2H,d, J=6.6 Hz), 8.73 (2H, d, J=6.6 Hz).

5) To a solution of(2RS,3RS)-3-hydroxy-3-(4-pyridyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionie acid (7.8 g, 24.0 mmol) in tetrahydrofuran (100 ml) were addeddiphenylphosphoryl azide (4.6 ml, 21.3 mmol) and triethylamine (6.76 ml,48.4 mmol), and the mixture was heated under reflux overnight. Thereaction solution was allowed to cool, water (200 ml) was added and themixture was extracted with ethyl acetate (200 ml×2). The extract waswashed with saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=1:1) and recrystallizedfrom diisopropyl ether-hexane to give(4RS,5SR)-5-(4-pyridyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(2.50 g, 58%).

mp 212-213° C. IR ν max^(KBr)cm⁻¹: 1755, 1609. Anal. Calcd forC₁₆H₁₃F₃N₂O₂: C, 59.63; H, 4.07; N, 8.69. Found: C, 59.71; H, 3.99; N,8.56. ¹H-NMR (CDCl₃)δ: 2.20-2.48 (2H, m), 4.26-4.38 (1H, m), 5.33 (1H,brs), 5.80 (1H, d, J=8.2 Hz), 7.16 (2H, d, J=8.0 Hz), 7.33 (2H, d, J=6.0Hz), 7.56 (2H, d, J=8.0 Hz), 7.68 (2H, d, J=6.0 Hz).

6) To a solution of(4RS,5SR)-5-(4-pyridyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(500 mg, 1.55 mmol) in acetonitrile (5 ml) were added di-t-butyldicarbonate (406 mg, 1.86 mmol) and dimethylaminopyridine (19.6 mg, 0.16mmol), and the mixture was stirred at room temperature for 1 hr. To thereaction solution was added water (20 ml) and the mixture was extractedwith ethyl acetate (20 ml×2). The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was recrystallized from ethylacetate-hexane to give 1,1-dimethylethyl(4RS,5SR)-2-oxo-5-(4-pyridyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidine-3-carboxylate(571 mg, 87%).

mp 166-168° C. IR ν max^(KBr)cm⁻¹: 1821, 1726. Anal. Calcd forC₂₁H₂₁F₃N₂O₄: C, 59.71; H, 5.01; N, 6.63. Found: C, 59.65; H, 5.05; N,6.34. ¹H-NMR (CDCl₃)δ: 1.48 (9H, s), 2.61 (1H, dd, J=14.2, 8.0 Hz), 2.91(1H, dd, J=14.2, 5.4 Hz), 4.80-4.98 (1H, m), 5.67 (1H, d, J=7.0 Hz),6.84 (2H, d, J=8.0 Hz), 7.13 (2H, d, J=6.0 Hz), 7.37 (2H, d, J=8.0 Hz),8.54 (2H, d, J=6.0 Hz).

7) To a solution of 1,1-dimethylethyl(4RS,5SR)-2-oxo-5-(4-pyridyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidine-3-carboxylate(500 mg, 1.18 mmol) in methanol (2.8 ml) was added 0.5N sodium hydroxide(2.8 ml, 1.40 mmol), and the mixture was stirred at room temperature for1 hr. To the reaction solution was added water (20 ml), and the mixturewas extracted with ethyl acetate (20 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was recrystallized from ethylacetate-hexane to give the title compound (391 mg, 83%).

mp 198-200° C. IR ν max^(KBr)cm⁻¹: 1682, 1605, 1528. ¹H-NMR (CDCl₃)δ:1.35 (9H, s), 2.72-2.82 (2H, m), 3.61 (1H, brs), 4.11 (1H, brs), 4.65(1H, d, J=8.6 Hz), 4.99 (1H, s), 7.20 (2H, d, J=8.0 Hz), 7.36 (2H, d,J=6.0 Hz), 7.51 (2H, d, J=8.0 Hz), 8.61 (2H, d, J=6.0 Hz)

Example 2004-fluoro-N-((1S,2R)-2-hydroxy-2-(4-pyridyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide

1) To 1,1-dimethylethyl(1RS,2SR)-2-hydroxy-2-(4-pyridyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethylcarbamate(300 mg, 0.76 mmol) was added trifluoroacetic acid (3 ml), and themixture was stirred at room temperature for 10 min. To the reactionsolution was added 1N aqueous sodium hydroxide solution (10 ml) and themixture was extracted with ethyl acetate (20 ml×2). The extract waswashed with saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-diisopropyl ether to give(1RS,2SR)-2-amino-1-(4-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(135 mg, 60%).

mp 97-98° C. IR ν max^(KBr)cm⁻¹: 1603, 1418. ¹H-NMR (CDCl₃)δ: 2.43 (1H,dd, J=13.6, 10.6 Hz), 2.71 (1H, dd, J=13.6, 2.8 Hz), 3.30-3.42 (1H, m),4.74 (1H, d, J=4.4 Hz), 7.23 (2H, d, J=8.2 Hz), 7.35 (2H, d, J=6.0 Hz),7.55 (2H, d, J=8.2 Hz), 8.62 (2H, d, J=6.0 Hz).

2) To a solution of(1RS,2SR)-2-amino-1-(4-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(70 mg, 0.24 mmol) in acetonitrile (5 ml) were added4-fluoronaphthalenecarboxylic acid (45 mg, 0.24 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (68 mg, 0.35mmol) and 1-hydroxy-1H-benzotriazole (36 mg, 0.24 mmol) and the mixturewas stirred overnight at room temperature. The reaction solution wasdiluted with water (100 ml) and extracted with ethyl acetate (100 ml×2).The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethyl acetate)and recrystallized from ethyl acetate-diisopropyl ether to give thetitle compound (55 mg, 50%).

mp 239-243° C. IR ν max^(KBr)cm⁻¹: 1638, 1620, 1603. ¹H-NMR(CDCl₃+CD₃OD)δ: 2.80-3.00 (2H, m), 4.70-4.92 (1H, m), 5.05 (1H, brs),7.00-7.60 (13H, m), 8.07 (1H, d, J=8.4 Hz), 8.50-8.62 (2H, m),

Example 201 1,1-dimethylethyl(1RS,2SR)-2-(6-chloro-3-pyridyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethylcarbamate

1) To a solution of 6-chloro-3-pyridinecarboxylic acid (10 g, 63.5 mmol)in tetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole(11.3 g, 69.8 mmol), and the mixture was heated under reflux for 30 min.The reaction solution was cooled and monoethyl malonate magnesium salt(10 g, 34.9 mmol) was added. The mixture was stirred at room temperaturefor 30 min. To the reaction solution was added water (200 ml) and themixture was extracted with ethyl acetate (200 ml×2). The extract waswashed with saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1) to give ethyl3-(6-chloro-3-pyridyl)-3-oxopropionate (9.28 g, 64%) as a brown oil.

IR ν max^(KBr)cm⁻¹: 1740, 1694, 1628, 1584. ¹H-NMR (CDCl₃)δ: 1.16(3H×3/5, t, J=7.4 Hz), 1.24 (3H×2/5, t, J=7.0 Hz), 3.88 (2H×3/5, s),4.04-4.24 (2H, m), 5.58 (1H×2/5; s), 7.29 (1H×2/5, d, J=8.0 Hz), 7.37(1H×3/5, d, J=8.0 Hz), 7.90 (1H×2/5, dd, J=8.0, 2.6 Hz), 8.11 (1H×3/5,dd, J=8.0, 2.6 Hz), 8.66 (1H×2/5, d, J=2.6 Hz), 8.81 (1H×3/5, d, J=2.6Hz).

2) To a solution of ethyl 3-(6-chloro-3-pyridyl)-3-oxopropionate (9.0 g,39.5 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60%in oil, 1.58 g, 39.5 mmol) under ice-cooling, and the mixture wasstirred at room temperature for 2 hrs. To the reaction solution wasdropwise added a solution of 4-trifluoromethylbenzyl bromide (9.45 g,39.5 mmol) in 1,2-dimethoxyethane (50 ml), and the mixture was stirredovernight at room temperature. The reaction solution was poured intowater (200 ml), saturated aqueous sodium hydrogen carbonate was added,and the mixture was extracted with ethyl acetate (200 ml×2). The extractwas washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (toluene:ethyl acetate=1:1)to give ethyl3-(6-chloro-3-pyridyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate(14.2 g, 93%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1740, 1694, 1582. ¹H-NMR (CDCl₃)δ: 1.13 (3H, t,J=7.0 Hz), 3.40 (2H, d, J=7.4 Hz), 4.12 (2H, q, J=7.0 Hz), 4.54 (1H, t,J=7.4 Hz), 7.35 (2H, d, J=8.4 Hz), 7.44 (1H, d, J=7.0 Hz), 7.53 (2H, d,J=8.4 Hz), 8.16-8.24 (1H, m), 8.95 (1H, d, J=2.6 Hz).

3) To a solution of zinc chloride (9.89 g, 72.6 mmol) in diethyl ether(150 ml) was added sodium borohydride (5.49 g, 145 mmol), and themixture was stirred at room temperature for 30 min. The insolublematerial was filtered off, and a solution of ethyl3-(6-chloro-3-pyridyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate(14 g, 36.3 mmol) in diethyl ether (50 ml) was added to the filtrate.The mixture was stirred at room temperature for 30 min. 1N Hydrochloricacid was added to the reaction solution under ice-cooling to quench thereaction and water (200 ml) was added. The mixture was extracted withethyl acetate (300 ml×2). The extract was washed with water andsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by medium pressuresilica gel column chromatography (hexane:ethyl acetate=4:1) to giveethyl(2RS,3RS)-3-(6-chloro-3-pyridyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate(9.32 g, 66%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1728, 1618, 1588, 1568. ¹H-NMR (CDCl₃)δ: 0.95 (3H,t, J=7.0 Hz), 2.92-3.18 (3H, m), 3.35 (1H, d, J=2.4 Hz), 3.92 (2H, q,J=7.0 Hz), 5.04-5.12 (1H, m), 7.20 (2H, d, J=8.2 Hz), 7.32 (1H, d, J=8.4Hz), 7.50 (2H, d, J=8.2 Hz), 7.73 (1H, dd, J=8.8, 2.8 Hz), 8.38 (1H, d,J=8.4 Hz).

4) To a solution ofethyl(2RS,3RS)-3-(6-chloro-3-pyridyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate(9.0 g, 23.2 mmol) in methanol (23 ml) was added 2N aqueous sodiumhydroxide solution (23.2 ml, 46.4 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid, and saturated aqueous sodium hydrogen carbonatewas added to adjust the pH to 8. The mixture was extracted with ethylacetate (200 ml×2). The extract was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was recrystallized from diisopropylether-hexane to give(2RS,3RS)-3-(6-chloro-3-pyridyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (7.4 g, 89%).

mp 145-146° C. IR ν max^(KBr)cm⁻¹: 1715, 1591, 1464. Anal. Calcd forC₁₆H₁₃NO₃ClF₃: C, 53.42; H, 3.64; N, 3.89. Found: C, 53.48; H, 3.93; N,3.66. ¹H-NMR (CDCl₃)δ: 2.90-3.20 (3H, m), 5.11 (1H, d, J=4.4 Hz), 7.24(2H, d, J=8.4 Hz), 7.33 (1H, d, J=8.2 Hz), 7.49 (2H, d, J=8.4 Hz), 7.78(1H, dd, J=8.2, 2.2 Hz), 8.35 (1H, d, J=2.2 Hz).

5) To a solution of(2RS,3RS)-3-(6-chloro-3-pyridyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (5.0 g, 13.9 mmol) in tetrahydrofuran (150 ml) were addeddiphenylphosphoryl azide (3.3 ml, 15.3 mmol) and triethylamine (2.9 ml,20.9 mmol), and the mixture was heated under reflux for 1 hr. Thereaction solution was allowed to cool and water (200 ml) was added. Themixture was extracted with ethyl acetate (200 ml×2). The extract waswashed successively with 1N hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate) and recrystallizedfrom ethyl acetate-hexane to give(4RS,5SR)-5-(6-chloro-3-pyridyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(4.29 g, 87%).

mp 176-177° C. IR ν max^(KBr)cm⁻¹: 1767, 1590, 1568. Anal. Calcd forC₁₆H₁₂N₂O₂ClF₃: C, 53.87; H, 3.39; N, 7.85. Found: C, 53.86; H, 3.57; N,7.66. ¹H-NMR (CDCl₃)δ: 2.22-2.50 (2H, m), 4.26-4.40 (1H, m), 5.16 (1H,brs), 5.84 (1H, d, J=8.0 Hz), 7.16 (2H, d, J=8.0 Hz), 7.43 (1H, d, J=8.2Hz), 7.57 (2H, d, J=8.0 Hz), 7.73 (1H, dd, J=8.2, 2.6 Hz), 8.41 (1H, d,J=2.6 Hz).

6) To a solution of(4RS,5SR)-5-(6-chloro-3-pyridyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(500 mg, 1.40 mmol) in acetonitrile (5 ml) were addeddi-t-butyl-dicarbonate (367 mg, 1.68 mmol) and dimethylaminopyridine (17mg, 0.14 mmol), and the mixture was stirred at room temperature for 2hrs. The reaction solution was concentrated, diluted with water (20 ml)and extracted with ethyl acetate (20 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was recrystallized from ethylacetate-hexane to give1,1-dimethylethyl(4RS,5SR)-5-(6-chloro-3-pyridyl)-2-oxo-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-3-carboxylate(1.19 g, 93%).

mp 170-174° C. IR ν max^(KBr)cm⁻¹: 1821, 1723, 1464, 1362. Anal. Calcdfor C₂₁H₂₀N₂O₄ClF₃: C, 55.21; H, 4.41; N, 6.13. Found: C, 55.44; H,4.28; N, 6.22. ¹H-NMR (CDCl₃)δ: 1.49 (9H, s), 2.60 (1H, dd, J=14.2, 8.8Hz), 3.01 (1H, dd, J=14.2, 5.2 Hz), 4.82-4.96 (1H, m), 5.70 (1H, d,J=7.0 Hz), 6.85 (2H, d, J=8.0 Hz), 7.18 (1H, d, J=8.4 Hz), 7.36-7.46(3H, m), 8.27 (1H, d, J=2.2 Hz).

7) To a solution of1,1-dimethylethyl(4RS,5SR)-5-(6-chloro-3-pyridyl)-2-oxo-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidine-3-carboxylate(600 mg, 1.31 mmol) in methanol (3.1 ml) was added 0.5N sodium hydroxidemethanol solution (3.1 ml, 1.55 mmol) under ice-cooling, and the mixturewas stirred at room temperature for 1 hr. To the reaction solution wasadded water (50 ml) and the mixture was extracted with ethyl acetate (50ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to give the title compound (321mg, 57%).

mp 157-158° C. IR ν max^(KBr)cm⁻¹: 1682, 1618, 1588, 1522. ¹H-NMR(CDCl₃)δ: 1.34 (9H, s), 2.70-2.90 (2H, m), 3.85 (1H, brs), 4.09 (1H,brs), 4.62 (1H, d, J=8.8 Hz), 4.96 (1H, s), 7.24 (2H, d, J=8.0 Hz), 7.35(1H, d, J=8.0 Hz), 7.53 (2H, d, J=8.0 Hz), 7.73 (1H, dd, J=8.0, 2.6 Hz),8.4 (1H, d, J=2.6 Hz).

Example 202N-((1RS,2SR)-2-(6-chloro-3-pyridyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-fluoro-1-naphthalenecarboxamide

1) To1,1-dimethylethyl(1RS,2SR)-2-(6-chloro-3-pyridyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethylcarbamate(880 mg, 2.04 mmol) was added trifluoroacetic acid (8 ml) at 0° C., andthe mixture was stirred for 10 min. The reaction solution wasconcentrated, diluted with water (20 ml) and extracted with ethylacetate (20 ml×2). The extract was washed with saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was recrystallized from ethyl acetate-diisopropyl ether togive(1RS,2SR)-2-amino-1-(6-chloro-3-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(602 mg, 89%).

mp 103-104° C. IR ν max^(KBr)cm⁻¹: 1588, 1568, 1460. Anal. Calcd forC₁₅H₁₄N₂OClF₃: C, 54.47; H, 4.27; N, 8.47. Found: C, 54.57; H, 4.19; N,8.39. ¹H-NMR (CDCl₃)δ: 2.42 (1H, dd, J=13.6, 10.4 Hz), 2.76 (1H, dd,J=13.6, 3.0 Hz), 3.30-3.44 (1H, m), 4.76 (1H, d, J=4.4 Hz), 7.24 (2H, d,J=8.4 Hz), 7.36 (1H, d, J=8.4 Hz), 7.55 (2H, d, J=8.4 Hz), 7.75 (1H, dd,J=8.4, 2.2 Hz).

2) To a solution of(1RS,2SR)-2-amino-1-(6-chloro-3-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(250 mg, 0.76 mmol) in acetonitrile (15 ml) were added4-fluoronaphthalenecarboxylic acid (144 mg, 0.76 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (218 mg,1.14 mmol) and 1-hydroxy-1H-benzotriazole (116 mg, 0.76 mmol), and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with water and saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was recrystallized from ethylacetate-hexane to give the title compound (324 mg, 85%).

mp 188-189° C. IR ν max^(KBr)cm⁻¹: 1642, 1626, 1601, 1534, 1462. Anal.Calcd for C₂₆H₁₉N₂O₂ClF₄.0.2H₂O: C, 61.66; H, 3.86; N, 5.53. Found: C,61.56; H, 3.91; N, 5.37. ¹H-NMR (CDCl₃)δ: 2.89 (1H, dd, J=14.6, 11.0Hz), 3.08 (1H, dd, J=14.6, 4.4 Hz), 4.04 (1H, brs), 4.68-4.84 (1H, m),5.13 (1H, d, J=3.6 Hz), 6.04 (1H, d, J=8.4 Hz), 6.92-7.20 (2H, m),7.22-7.70 (8H, m), 7.82 (1H, dd, J=8.0, 2.6 Hz), 8.09 (1H, d, J=8.0 Hz),8.44 (1H, d, J=2.6 Hz).

Example 203N-((1RS,2SR)-2-(6-chloro-3-pyridyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-3-phenylpropanamide

To a solution of(1RS,2SR)-2-amino-1-(6-chloro-3-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(250 mg, 0.76 mmol) in ethyl acetate (10 ml) were added3-phenylpropionyl chloride (168 ml, 1.13 mmol) and saturated aqueoussodium hydrogen carbonate (10 ml), and the mixture was stirred overnightat room temperature. The reaction solution was diluted with water (100ml) and extracted with ethyl acetate (100 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the title compound (302 mg, 86%).

mp 149-150° C. IR ν max^(KBr)cm⁻¹: 1651, 1541, 1456. Anal. Calcd forC₂₄H₂₂N₂O₂ClF₃: C, 62.27; H, 4.79; N, 6.05. Found: C, 62.44; H, 4.96; N,6.05. ¹H-NMR (CDCl₃)δ: 2.30-2.50 (2H, m), 2.60-2.92 (4H, m), 3.90 (1H,s), 4.24-4.40 (1H, m), 4.80-4.90 (1H, m), 5.36 (1H, d, J=8.2 Hz),7.00-7.40 (8H, m), 7.48 (2H, d, J=8.0 Hz), 7.56 (1H, dd, J=8.0, 2.6 Hz),8.32 (1H, d, J=2.2 Hz).

Example 2041,1-dimethylethyl(1RS,2RS)-2-(6-chloro-2-pyridyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethylcarbamate

1) To a solution of 6-chloro-2-pyridinecarboxylic acid (10 g, 63.5 mmol)in tetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole(11.3 g, 69.8 mmol), and the mixture was heated under reflux for 30 min.The reaction solution was cooled, and monoethyl malonate magnesium salt(10 g, 34.9 mmol) was added. The mixture was stirred at room temperaturefor 30 min. To the reaction solution was added water (200 ml) and themixture was extracted with ethyl acetate (200 ml×2). The extract waswashed with saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl-acetate=4:1) to give ethyl3-(6-chloro-2-pyridyl)-3-oxopropionate (7.96 g, 55%) as a brown oil. IRν max^(KBr)cm⁻¹: 1738, 1713, 1651, 1645. Anal. Calcd for C₁₀H₁₀NO₃Cl: C,52.76; H, 4.43; N, 6.15. Found: C, 52.63; H, 4.55; N, 6.02. ¹H-NMR(CDCl₃)δ: 1.20-1.40 (3H, m), 4.15 (2H×2/3, s), 4.14-4.32 (2H, m), 6.35(1H×1/3, s), 7.37 (1H×1/3, d, J=6.6 Hz), 7.53 (1H×2/3, d, J=7.0 Hz),7.70-8.02 (2H, m), 12.31 (1H×1/3, s).

2) To a solution of ethyl 3-(6-chloro-2-pyridyl)-3-oxopropionate (7.6 g,33.4 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60%in oil, 1.34 g, 33.4 mmol) under ice-cooling, and the mixture wasstirred at room temperature for 2 hrs. To the reaction solution wasdropwise added a solution of 4-trifluoromethylbenzyl bromide (7.98 g,33.4 mmol) in 1,2-dimethoxyethane (50 ml), and the mixture was stirredovernight at room temperature. The reaction solution was poured intowater (200 ml), saturated aqueous sodium hydrogen carbonate was added,and the mixture was extracted with ethyl acetate (200 ml×2). The extractwas washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (toluene) to give ethyl3-(6-chloro-2-pyridyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate(13.0 g, 100%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1732, 1709, 1576, 1563. ¹H-NMR (CDCl₃)δ: 1.14 (3H,t, J=7.0 Hz), 3.24-3.50 (2H, m), 4.02-4.20 (2H, m), 4.99 (1H, t, J=7.2Hz), 7.42 (2H, d, J=8.0 Hz), 7.52 (2H, d, J=8.0 Hz), 7.81 (1H, t, J=8.0Hz), 7.97 (1H, d, J=6.6 Hz).

3) To a solution of zinc chloride (9.0 g, 66.15 mmol) in diethyl ether(200 ml) was added sodium borohydride (5.0 g, 132 mmol), and the mixturewas stirred at room temperature for 30 min. The insoluble material wasfiltered off to give a solution of zinc borohydride in diethyl ether. Toa solution of ethyl3-(6-chloro-2-pyridyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate(12.7 g, 33.1 mmol) in diethyl ether (100 ml) was dropwise added slowlyat −20° C. the solution of zinc borohydride in diethyl ether prepared inadvance. The reaction solution was stirred at −20° C. for 30 min., and1N hydrochloric acid was added to quench the reaction. Water (200 ml)was added and the mixture was extracted with ethyl acetate (300 ml×2).The extract was washed with water and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1) to give ethyl3-(6-chloro-2-pyridyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate(4.1 g, 32%, (2RS,3RS) form: (2RS,3SR)form=1:1, crude) as a colorlessoil.

¹H-NMR (CDCl₃)δ: 0.95-1.10 (3H, m), 2.80-3.40 (3H, m), 3.82-4.08 (2H,m), 4.78 (1H×1/2, dd, J=9.6, 4.4 Hz), 5.08 (1H×1/2, t, J=5.0 Hz),7.10-7.70 (7H, m).

4) To a solution of ethyl3-(6-chloro-2-pyridyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate(4.1 g, 10.7 mmol) in methanol (20 ml) was added 2N aqueous sodiumhydroxide solution (10.7 ml, 21.4 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate wasadded to adjust the pH to 8, and the mixture was extracted with ethylacetate (200 ml×2). The extract was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was recrystallized from diisopropylether-hexane to give3-(6-chloro-2-pyridyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (3.3 g, 86%, (2RS,3RS) form: (2RS,3SR) form=1:1).

¹H-NMR (CDCl₃)δ: 2.20-2.60 (1H, m), 2.80-3.30 (2H, m), 4.73 (1H×1/2, d,J=7.4 Hz), 5.30 (1H×1/2, s), 6.64-7.40 (7H, m).

5) To a solution of3-(6-chloro-2-pyridyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (3.1 g, 8.6 mmol) in tetrahydrofuran (100 ml) were addeddiphenylphosphoryl azide (2.0 ml, 9.5 mmol) and triethylamine (1.8 ml,12.9 mmol), and the mixture was heated under reflux for 1 hr. Thereaction solution was allowed to cool, water (150 ml) was added, and themixture was extracted with ethyl acetate (150 ml×2). The extract waswashed successively with saturated aqueous sodium hydrogen carbonate andsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was recrystallized from diisopropylether-hexane to give5-(6-chloro-2-pyridyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(1.18 g, 38%, (4RS,5RS) form: (4RS,5SR) form=3:2).

¹H-NMR (CDCl₃)δ: 2.18 (1H×3/5, dd, J=13.4, 7.0 Hz), 2.62 (1H×3/5, dd,J=13.4, 3.8 Hz), 3.05 (1H×2/5, dd, J=13.4, 9.2 Hz), 3.36 (1H×2/5, dd,J=13.4, 4.4 Hz), 4.16-4.30 (1H×2/5, m), 4.40-4.56 (1H×3/5,m), 5.19(1H×3/5, s), 5.29 (1H×2/5, d, J=5.0 Hz), 5.37 (1H×2/5, s), 5.83 (1H×3/5,d, J=8.0 Hz), 7.10-7.82 (7H, m).

6) To a solution of5-(6-chloro-2-pyridyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(1.08 g, 1.40 mmol, (4RS,5RS) form: (4RS,5SR) form=3:2) in acetonitrile(10 ml) were added di-t-butyl dicarbonate (793 mg, 3.63 mmol) anddimethylaminopyridine (37 mg, 0.30 mmol), and the mixture was stirred atroom temperature for 30 min. The reaction solution was concentrated,diluted with water (20 ml), and extracted with ethyl acetate (20 ml×2).The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waseluted with hexane:ethyl acetate=4:1 by silica gel column chromatographyand recrystallized from diisopropyl ether-hexane to give1,1-dimethylethyl(4RS,5SR)-5-(6-chloro-2-pyridyl)-2-oxo-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidine-3-carboxylate(300 mg, 22%).

IR ν max^(KBr)cm⁻¹: 1817, 1726, 1566. mp 125-126° C. ¹H-NMR (CDCl₃)δ:1.55 (9H, s), 3.24 (1H, dd, J=13.6, 8.0 Hz), 3.44 (1H, dd, J=13.6, 4.4Hz), 4.76-4.86 (1H, m), 5.13 (1H, d, J=2.6 Hz), 7.22-7.32 (2H, m), 7.40(2H, d, J=8.0 Hz), 7.62 (2H, d, J=8.0 Hz), 7.66 (1H, t, j=7.8 Hz).

Further, the residue was eluted with hexane:ethyl acetate=1:1, andrecrystallized from ethyl acetate-hexane to give1,1-dimethylethyl(4RS,5RS)-5-(6-chloro-2-pyridyl)-2-oxo-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidine-3-carboxylate(735 mg, 53%).

IR ν max^(KBr)cm⁻¹: 1823, 1726, 1566. mp 166-167° C. ¹H-NMR (CDCl₃)δ:1.44 (9H, s), 2.65 (1H, dd, J=14.0, 8.0 Hz), 2.89 (1H, dd, J=14.0, 5.4Hz), 5.02-5.16 (1H, m), 5.66 (1H, d, J=6.6 Hz), 6.88 (2H, d, J=8.2 Hz),7.26 (1H, d, J=8.2 Hz), 7.40 (2H, d, J=8.0 Hz), 7.50 (1H, d, J=7.6 Hz),7.73 (1H, t, J=7.8 Hz).

7) To1,1-dimethylethyl(4RS,5RS)-5-(6-chloro-2-pyridyl)-2-oxo-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidine-3-carboxylate(677 mg, 1.46 mmol) in methanol (3.5 ml) was added 0.5N sodium hydroxidemethanol solution (3.5 ml, 1.75 mmol) under ice-cooling, and the mixturewas stirred at room temperature for 1 hr. To the reaction solution wasadded water (50 ml), and the mixture was extracted with ethyl acetate(50 ml×2). The extract was washed with saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethyl acetate)and recrystallized from diisopropyl ether-hexane to give the titlecompound (550 mg, 57%).

IR ν max^(KBr)cm⁻¹: 1682, 1530. mp 159-160° C. ¹H-NMR (CDCl₃)δ: 1.36(9H, s), 2.67 (1H, dd, J=15.0, 5.8 Hz), 2.87 (1H, dd, J=15.0, 8.4 Hz),4.12-4.30 (1H, m), 4.60 (1H, d, J=5.6 Hz), 4.90-5.10 (2H, m), 7.19 (2H,d, J=7.8 Hz), 7.20-7.32 (2H, m), 7.45 (2H, d, J=7.8 Hz), 7.61 (1H, t,J=8.0 Hz).

Example 205N-((1RS,2RS)-2-(6-chloro-2-pyridyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-fluoro-1-naphthalenecarboxamide

1) To1,1-dimethylethyl(1RS,2RS)-2-(6-chloro-2-pyridyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethylcarbamate(500 mg, 1.16 mmol) was added trifluoroacetic acid (8 ml) at 0° C., andthe mixture was stirred for 10 min. The reaction solution wasconcentrated, diluted with water (20 ml) and extracted with ethylacetate (20 ml×2). The extract was washed with saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was recrystallized from diisopropyl ether-hexane to give(1RS,2RS)-2-amino-1-(6-chloro-2-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(302 mg, 79%).

IR ν max^(KBr)cm⁻¹: 1757, 1586, 1563. mp 89-90° C. ¹H-NMR (CDCl₃)δ: 2.54(1H, dd, J=13.6, 9.8 Hz), 2.77 (1H, d, J=13.0 Hz), 3.44-3.58 (1H, m),4.74 (1H, d, J=4.4 Hz), 7.16-7.32 (3H, m), 7.57 (1H, d, J=7.4 Hz), 7.52(2H, d, J=7.4 Hz), 7.62-7.74 (1H, m).

2) To a solution of(1RS,2RS)-2-amino-1-(6-chloro-2-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(250 mg, 0.76 mmol) in acetonitrile (15 ml) were added4-fluoronaphthalenecarboxylic acid (144 mg, 0.76 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (218 mg,1.14 mmol) and 1-hydroxy-1H-benzotriazole (116 mg, 0.76 mmol), and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with water and saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1). Recrystallization from ethylacetate-hexane gave the title compound (267 mg, 70%).

mp 225-226° C. IR ν max^(KBr)cm⁻¹: 1639, 1624. ¹H-NMR (CDCl₃)δ: 2.83(1H, dd, J=14.0, 5.2 Hz), 3.02 (1H, dd, J=14.0, 9.6 Hz), 4.74 (1H, d,J=5.6 Hz), 4.80-5.00 (1H, m), 5.10-5.20 (1H, m), 6.46 (1H, d, J=8.6 Hz),7.00-7.12 (1H, m), 7.20-7.60 (9H, m), 7.64-7.76 (1H, m), 7.84 (1H, d,J=7.6 Hz), 8.11 (1H, d, J=8.0 Hz).

Example 2061,1-dimethylethyl(1RS,2SR)-2-(6-chloro-2-pyridyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethylcarbamate

To a solution of1,1-dimethylethyl(4RS,5SR)-5-(6-chloro-2-pyridyl)-2-oxo-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidine-3-carboxylate(237 mg, 0.52 mmol) in methanol (1.25 ml) was added 0.5N sodiumhydroxide methanol solution (1.25 ml, 0.62 mmol) under ice-cooling, andthe mixture was stirred at room temperature for 1 hr. To the reactionsolution was-added water (50 ml) and the mixture was extracted withethyl acetate (50 ml×2). The extract was washed with saturated brine,dried over anhydrous magnesium sulfate and evaporated under reducedpressure. The residue was recrystallized from ethyl acetate-hexane togive the title compound (150 mg, 67%).

IR ν max^(KBr)cm⁻¹: 1694, 1505. mp 134-135° C. ¹H-NMR (CDCl₃)δ: 1.24(9H, s), 3.13 (2H, d, J=7.8 Hz), 4.10-4.30 (1H, m), 4.62-4.90 (2H, m),7.20-7.30 (2H, m), 7.30-7.52 (2H, m), 7.56-7.72 (3H, m).

Example 207N-((1RS,2SR)-2-hydroxy-2-(3-phenoxyphenyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-fluoro-1-naphthalenecarboxamide.

1) To a solution of 3-phenoxybenzoic acid (13.5 g, 63.0 mmol) intetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole (11.2g, 69.3 mmol), and the mixture was stirred at room temperature for 30min. To the reaction solution was added monoethyl malonate magnesiumsalt (10 g, 34.8 mmol) and the mixture was stirred at room temperaturefor 2 hrs. To the reaction solution were added ethyl acetate (50 ml) andwater (50 ml), and conc. hydrochloric acid was added until the pH of theaqueous layer became acidic. The reaction solution was extracted withethyl acetate (200 ml×2). The extract was washed with saturated brine,dried over anhydrous magnesium sulfate and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1) to give ethyl3-oxo-3-(4-phenoxyphenyl)propionate (17.9 g, 100%) as a brown oil.

IR ν max^(KBr)cm⁻¹: 1744, 1694, 1582, 1489, 1439. Anal. Calcd forC₁₇H₁₆O₄.0.1H₂O: C, 71.37; H, 5.70 Found: C, 71.11; H, 5.89. ¹H-NMR(CDCl₃)δ: 1.20-1.40 (3H, m), 3.95 (2H×4/5, s), 4.12-4.30 (2H, m), 5.62(1H×1/5, s), 7.02 (2H, d, J=7.4 Hz), 7.04-7.30 (2H, m), 7.30-7.60 (4H,m), 7.66 (1H, d, J=7.6 Hz).

2) To a solution of ethyl 3-oxo-3-(4-phenoxyphenyl)propionate (15 g,52.8 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60%in oil, 2.11 g, 52.8 mmol) under ice-cooling, and the mixture wasstirred at room temperature for 30 min. To the reaction solution wasdropwise added a solution of 4-trifluoromethylbenzyl bromide (12.6 g,52.8 mmol) in 1,2-dimethoxyethane (50 ml), and the mixture was stirredat room temperature for 4 hrs. The reaction solution was poured intowater (200 ml) and extracted with ethyl acetate (200 ml×2). The extractwas washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to give ethyl3-oxo-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate(15.4 g, 66%).

mp 77-78° C. IR ν max^(KBr)cm⁻¹: 1738, 1694, 1582, 1489, 1437. Anal.Calcd for C₂₅H₂₁F₃O₄: C, 67.87; H, 4.78 Found: C, 67.92; H, 4.89. ¹H-NMR(CDCl₃)δ: 1.10 (3H, t, J=7.4 Hz), 3.35 (1H, d, J=7.4 Hz), 4.09 (2H, q,J=7.4 Hz), 4.53 (1H, t, J=7.4 Hz), 6.94-7.04 (2H, m), 7.10-7.70 (11H,m).

3) To a solution of zinc chloride (7.39 g, 54.2 mmol) in diethyl ether(150 ml) was added sodium borohydride (4.11 g, 108.5 mmol), and themixture was stirred at room temperature for 30 min. The insolublematerial was filtered off, and a solution of ethyl3-oxo-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate(10 g, 25.9 mmol) in diethyl ether (50 ml) was added to the filtrate.The mixture was stirred at room temperature for 30 min. 1N Hydrochloricacid was added to the reaction solution under ice-cooling to quench thereaction. Water (200 ml) was added, and the mixture was extracted withethyl acetate (300 ml×2). The extract was washed with water andsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate) to giveethyl(2RS,3RS)-3-hydroxy-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate(12.0 g, 100%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1728, 1713, 1584, 1487, 1447. Anal. Calcd forC₂₅H₂₃F₃O₄: C, 67.56; H, 5.22 Found: C, 67.46; H, 5.20 ¹H-NMR (CDCl₃)δ:0.94 (3H, t, J=7.2 Hz), 2.90-3.12 (4H, m), 3.90 (2H, q, J=7.2 Hz),4.98-5.08 (1H, m), 6.90-7.40 (11H, m), 7.48 (2H, d, J=8.0 Hz).

4) To a solution ofethyl(2RS,3RS)-3-hydroxy-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate(11.8 g, 26.6 mmol) in methanol (40 ml) was added 2N aqueous sodiumhydroxide solution (26.6 ml, 53.2 mmol), and the mixture was stirred atroom temperature for 4 hrs. The reaction solution was acidified with 1Nhydrochloric acid and extracted with ethyl acetate (200 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to give(2RS,3RS)-3-hydroxy-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (9.0 g, 81%).

mp 128-129° C. IR ν max^(KBr)cm⁻¹: 1713, 1586, 1489, 1447. Anal. Calcdfor C₂₃H₁₉F₃O₄: C, 66.34; H, 4.60 Found: C, 66.41; H, 4.58. ¹H-NMR(CDCl₃)δ: 2.86-3.14 (3H, m), 5.10 (1H, s), 6.90-7.02 (3H, m), 7.02-7.22(5H, m), 7.22-7.40 (3H, m), 7.47 (2H, d, J=8.0 Hz).

5) To a solution of(2RS,3RS)-3-hydroxy-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (7.0 g, 16.8 mmol) in tetrahydrofuran (180 ml) were addeddiphenylphosphoryl azide (4.0 ml, 18.5 mmol) and triethylamine (3.5 ml,25.2 mmol), and the mixture was heated under reflux for 6 hrs. Thereaction solution was allowed to cool and water (200 ml) was added. Themixture was extracted with ethyl acetate (200 ml×2). The extract waswashed successively with 1N hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate) and recrystallizedfrom ethyl acetate-hexane to give(4RS,5SR)-5-(4-phenoxyphenyl)-4-((4-(trifluoromethyl)phenyl)-methyl)-1,3-oxazolidin-2-one(6.40 g, 92%).

mp 110-111° C. IR ν max^(KBr)cm⁻¹: 1759, 1617, 1586, 1489. Anal. Calcdfor C₂₃H₁₈F₃NO₃: C, 66.82; H, 4.39; N, 3.39. Found: C, 66.78; H, 4.25;N, 3.14. ¹H-NMR (CDCl₃)δ: 2.30-2.50 (2H, m), 4.18-4.30 (1H, m), 5.22(1H, s), 5.77 (1H, d, J=8.0 Hz), 6.96-7.04 (4H, m), 7.04-7.20 (4H, m),7.30-7.44 (3H, m), 7.55 (2H, d, J=8.0 Hz).

6) To a solution of(4RS,5SR)-5-(4-phenoxyphenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(6.0 g, 14.5 mmol) in ethanol (100 ml) was added 8N aqueous sodiumhydroxide solution (9.0 ml, 72 mmol), and the mixture was heated underreflux for 4 hrs. The reaction solution was concentrated, diluted withwater (300 ml) and extracted with ethyl acetate (300 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure to give(1RS,2SR)-2-amino-1-(4-phenoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(4.21 g, 75%) as a colorless oil. A portion thereof was recrystallizedfrom ethanol-ether as hydrochloride, which was measured for elementalanalysis values.

IR ν max^(KBr)cm⁻¹: 1584, 1489, 1443, 1418. Anal. Calcd forC₂₂H₂₁ClF₃NO₂.0.2H₂O: C, 61.82; H, 5.04; N, 3.28. Found: C, 61.83; H,5.26; N, 3.24. ¹H-NMR (CDCl₃)δ: 2.44 (1H, dd, J=14.2, 10.2 Hz), 2.86(1H, dd, J=14.0, 2.8 Hz), 3.20-3.36 (1H, m), 4.64 (1H, d, J=4.8 Hz),6.90-7.20 (6H, m), 7.20-7.42 (5H, m), 7.53 (2H, d, J=8.0 Hz).

7) To a solution of(1RS,2SR)-2-amino-1-(4-phenoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(400 mg, 1.03 mmol) in acetonitrile (30 ml) were added4-fluoronaphthalenecarboxylic acid (196 mg, 1.03 mmol),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (247 mg,1.55 mmol) and 1-hydroxy-1H-benzotriazole (158 mg, 1.03 mmol), and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure.Recrystallization of the residue from ethyl acetate-hexane gave thetitle compound (446 mg, 77%).

mp 184-185° C. IR ν max^(KBr)cm⁻¹: 1642, 1537, 1489. Anal. Calcd forC₃₃H₂₅F₄NO₃: C, 70.83; H, 4.50; N, 2.50. Found: C, 70.65; H, 4.56; N,2.44. ¹H-NMR (CDCl₃)δ: 2.88 (1H, dd, J=14.4, 10.6 Hz), 3.08 (1H, dd,J=14.4, 4.0 Hz), 4.76-4.94 (1H, m), 5.09 (1H, s), 6.04 (1H, d, J=8.8Hz), 6.95-7.50 (14H, m), 7.50-7.60 (3H, m), 7.66 (1H, d, J=8.0 Hz), 8.10(1H, d, J=8.4 Hz).

Example 208N-((1RS,2SR)-2-hydroxy-2-(3-phenoxyphenyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-3-phenylpropanamide

To a solution of(1RS,2SR)-2-amino-1-(4-phenoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(400 mg, 1.03 mmol) in ethyl acetate (20 ml) were added3-phenylpropionyl chloride (230 ml, 1.55 mmol) and saturated aqueoussodium hydrogen carbonate (20 ml), and the mixture was stirred overnightat room temperature. The reaction solution was diluted with water (100ml) and extracted with ethyl acetate (100 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the title compound (472 mg, 88%).

mp 134-135° C. IR ν max^(KBr)cm⁻¹: 1645, 1584, 1489, 1445. Anal. Calcdfor C₃₁H₂₈F₃NO₃: C, 71.66; H, 5.43; N, 2.70. Found: C, 71.50; H, 5.47;N, 2.43. ¹H-NMR (CDCl₃)δ: 2.37 (2H, t, J=7.6 Hz), 2.58-2.78 (2H, m),2.85 (2H, t, J=7.6 Hz), 3.20 (1H, d, J=3.8 Hz), 4.30-4.48 (1H, m),4.78-4.84 (1H, m), 5.37 (1H, d, J=8.4 Hz), 6.90-7.20 (10H, m), 7.20-7.40(6H, m), 7.45 (2H, d, J=8.4 Hz).

Example 209N-((1RS,2SR)-2-hydroxy-2-(4-phenoxyphenyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-4-fluoro-1-naphthalenecarboxamide

1) To a solution of 4-phenoxybenzoic acid (10.4 g, 48.7 mmol) intetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole (8.68g, 53.6 mmol), and the mixture was stirred at room temperature for 30min. To the reaction solution was added monoethyl malonate magnesiumsalt (7.67 g, 26.8 mmol), and the mixture was stirred at roomtemperature for 2 hrs. Ethyl acetate (50 ml) and water (50 ml) wereadded to the reaction solution and conc. hydrochloric acid was addeduntil the aqueous layer showed acidic pH. The reaction solution wasextracted with ethyl acetate (200 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) to give ethyl3-oxo-3-(4-phenoxyphenyl)propionate (12.9 g, 93%) as a brown oil.

IR ν max^(KBr)cm⁻¹: 1738, 1682, 1586, 1505, 1489. Anal. Calcd forC₁₇H₁₆O₄: C, 71.82; H, 5.67 Found: C, 71.63; H, 5.56. ¹H-NMR (CDCl₃)δ:1.20-1.38 (3H, m), 3.95 (2H×5/6, s), 4.16-4.32 (2H, m), 5.60 (1H×1/6,s), 6.94-7.12 (4H, m), 7.12-7.28 (1H, m), 7.32-7.48 (2H, m), 7.72-7.80(2H×1/6, m), 7.88-8.00 (2H×5/6, m).

2) To a solution of ethyl 3-oxo-3-(4-phenoxyphenyl)propionate (12 g,42.2 mmol) in 1,2-dimethoxyethane (80 ml) was added sodium hydride (60%in oil, 1.69 g, 42.2 mmol) under ice-cooling, and the mixture wasstirred at room temperature for 30 min. To the reaction solution wasdropwise added a solution of 4-trifluoromethylbenzyl bromide (10.1 g,42.2 mmol) in 1,2-dimethoxyethane (50 ml), and the reaction solution wasstirred at room temperature for 4 hrs. The reaction solution was pouredinto water (200 ml), and extracted with ethyl acetate (200 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to give ethyl3-oxo-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate(14.0 g, 75%).

mp 67-68° C. IR ν max^(KBr)cm⁻¹: 1738, 1682, 1586, 1505, 1489. Anal.Calcd for C₂₅H₂₁F₃O₄: C, 67.87; H, 4.78 Found: C, 67.88; H, 4.89. ¹H-NMR(CDCl₃)δ: 1.13 (3H, t, J=7.2 Hz), 3.37 (2H, d, J=7.2 Hz ), 4.11 (2H, q,J=7.2 Hz), 4.57 (1H, t, J=7.2 Hz), 6.90-7.10 (4H, m), 7.12-7.26 (1H, m),7.30-7.48 (4H, m), 7.51 (2H, d, J=8.2 Hz), 7.90-8.00 (2H, m).

3) To a solution of zinc chloride (7.39 g, 54.2 mmol) in diethyl ether(150 ml) was added sodium borohydride (4.11 g, 108.5 mmol) and themixture was stirred at room temperature for 30 min. Insoluble materialwas filtered off and a solution of ethyl3-oxo-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate(12 g, 27.1 mmol) in diethyl ether (50 ml) was added to the filtrate.The mixture was stirred at room temperature for 30 min. 1N Hydrochloricacid was added to the reaction solution under ice-cooling to quench thereaction. Water (200 ml) was added and the mixture was extracted withethyl acetate (300 ml×2). The extract was washed with water andsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate) to giveethyl(2RS,3RS)-3-hydroxy-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate(11.9 g, 99%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1728, 1618, 1590, 1507, 1489. Anal. Calcd forC₂₅H₂₃F₃O₄: C, 67.56; H, 5.22 Found: C, 67.40; H, 5.04. ¹H-NMR (CDCl₃)δ:0.94 (3H, t, J=7.2 Hz), 2.85 (1H, d, J=2.6 Hz), 2.90-3.12 (3H, m), 3.89(2H, q, J=7.2 Hz), 4.98-5.06 (1H, m), 6.94-7.04 (4H, m), 7.04-7.18 (1H,m), 7.22 (2H, d, J=8.0 Hz), 7.30-7.42 (4H, m), 7.49 (2H, d, J=8.0 Hz).

4) To a solution ofethyl(2RS,3RS)-3-hydroxy-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate(11.5 g, 25.9 mmol) in methanol (40 ml) was added 2N aqueous sodiumhydroxide solution (25.9 ml, 51.8 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to give(2RS,3RS)-3-hydroxy-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (9.65 g, 90%).

mp 140-141° C. IR ν max^(KBr)cm⁻¹: 1715, 1590, 1489. Anal. Calcd forC₂₃H₁₉F₃O₄: C, 66.34; H, 4.60 Found: C, 66.36; H, 4.49. ¹H-NMR (CDCl₃)δ:2.98-3.10 (3H, m), 5.08 (1H, s), 6.92-7.04 (4H, m), 7.04-7.30 (3H, m),7.30-7.40 (4H, m), 7.48 (2H, d, J=8.2 Hz).

5) To a solution of(2RS,3RS)-3-hydroxy-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionicacid (7.0 g, 16.8 mmol) in tetrahydrofuran (180 ml) were addeddiphenylphosphoryl azide (4.0 ml,18.5 mmol) and triethylamine (3.5 ml,25.2 mmol), and the mixture was heated under reflux for 6 hrs. Thereaction solution was allowed to cool and water (200 ml) was added. Themixture was extracted with ethyl acetate (200 ml×2). The extract waswashed successively with 1N hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel-column chromatography (ethyl acetate) and recrystallizedfrom ethyl acetate-hexane to give(4RS,5SR)-5-(4-phenoxyphenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(6.40 g, 92%).

mp 162-163° C. IR ν max^(KBr)cm⁻¹: 1759, 1617, 1591, 1508, 1489. Anal.Calcd for C₂₃H₁₈F₃NO₃: C, 66.82; H, 4.39; N, 3.39. Found: C, 66.94; H,4.17; N, 3.39. ¹H-NMR (CDCl₃)δ: 2.30-2.50 (2H, m), 4.20-4.32 (1H, m),5.11 (1H, brs), 5.80 (1H, d, J=7.8 Hz), 6.90-7.10 (4H, m), 7.10-7.22(3H, m), 7.22-7.50 (4H, m), 7.56 (2H, d, J=8.0 Hz).

6) To a solution of(4RS,5SR)-5-(4-phenoxyphenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one(6.0 g, 14.5 mmol) in ethanol (100 ml) was added 8N aqueous sodiumhydroxide solution (9.0 ml, 72 mmol), and the mixture was heated underreflux for 4 hrs. The reaction solution was concentrated and dilutedwith water (300 ml). The mixture was extracted with ethyl acetate (300ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to give(1RS,2SR)-2-amino-1-(4-phenoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(5.03 g, 90%).

mp 114-115° C. IR ν max^(KBr)cm⁻¹: 1590, 1507, 1489. Anal. Calcd forC₂₂H₂₀F₃NO₂: C, 68.21; H, 5.20; N, 3.62. Found: C, 68.12; H, 5.27; N,3.58. ¹H-NMR (CDCl₃)δ: 2.46 (1H, dd, J=13.6, 10.2 Hz), 2.94 (1H, dd,J=13.6, 2.8 Hz), 3.24-3.38 (1H, m), 4.65. (1H, d, J=5.0 Hz), 6.98-7.18(5H, m), 7.22-7.42 (6H, m), 7.55 (2H, d, J=8.0 Hz).

7) To a solution of(1RS,2SR)-2-amino-1-(4-phenoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(400 mg, 1.03 mmol) in acetonitrile (30 ml) were added4-fluoronaphthalenecarboxylic acid (196 mg, 1.03 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (297 mg,1.55 mmol) and 1-hydroxy-1H-benzotriazole (158 mg, 1.03 mmol), and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure.Recrystallization of the residue from ethyl acetate-hexane gave thetitle compound (520 mg, 90%).

mp 205-210° C. IR ν max^(KBr)cm⁻¹: 1644, 1626, 1599, 1510. Anal. Calcdfor C₃₃H₂₅F₄NO₃: C, 70.83; H, 4.50; N 2.50 Found: C, 70.59; H, 4.50; N,2.57. ¹H-NMR (CDCl₃)δ: 2.89 (1H, dd, J=14.2, 11.0 Hz), 3.06-3.24 (2H,m), 4.78-4.90 (1H, m), 5.09 (1H, d, J=4.0 Hz), 5.97 (1H, d, J=9.0 Hz),6.96-7.20 (7H, m), 7.30-7.68 (11H, m), 8.08 (1H, d, J=8.0 Hz).

Example 210N-((1RS,2SR)-2-hydroxy-2-(4-phenoxyphenyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-1-(4-phenoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(206 mg, 0.53 mmol) in acetonitrile (20 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (100 mg, 0.53mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153mg, 0.80 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with 1Nhydrochloric acid, 1N aqueous sodium hydroxide solution and saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. Recrystallization of the residue from ethylacetate-hexane gave the title compound (268 mg, 90%).

mp 191-192° C. IR ν max^(KBr)cm⁻¹: 1642, 1590, 1507, 1489, 1327. ¹H-NMR(CDCl₃)δ: 1.90-2.06 (2H, m), 2.10-2.26 (2H, m), 2.60-2.70 (2H, m), 2.85(1H, dd, J=14.4, 11.0 Hz), 3.07 (1H, dd, J=14.4, 3.4 Hz), 3.42 (1H,brs), 4.64-4.84 (1H, m), 5.03 (1H, d, J=4.0 Hz), 5.80 (1H, d, J=9.6 Hz),5.80-5.96 (1H, m), 6.13 (1H, d, J=11.8 Hz), 6.90-7.20 (8H, m), 7.20-7.50(6H, m), 7.54 (2H, d, J=8.2 Hz).

Example 211N-((1RS,2SR)-2-hydroxy-2-(4-phenoxyphenyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-3-phenylpropanamide

To a solution of(1RS,2SR)-2-amino-1-(4-phenoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol(400 mg, 1.03 mmol) in ethyl acetate (20 ml) were added3-phenylpropionyl chloride (230 ml, 1.55 mmol) and saturated aqueoussodium hydrogen carbonate (20 ml), and the mixture was stirred overnightat room temperature. The reaction solution was diluted with water (100ml) and extracted with ethyl acetate (100 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the title compound (416 mg, 78%).

mp 133-134° C. IR ν max^(KBr)cm⁻¹: 1645, 1590, 1507, 1489. Anal. Calcdfor C₃₁H₂₈F₃NO₃: C, 71.66; H, 5.43; N, 2.70. Found: C, 71.84; H, 5.26;N, 2.69. ¹H-NMR (CDCl₃)δ: 2.32-2.42 (2H, m), 2.60-2.90 (4H, m),3.14-3.22 (1H, m), 4.32-4.50 (1H, m), 4.78-4.86 (1H, m), 5.36 (1H, d,J=8.4 Hz), 6.92-7.04 (4H, m), 7.06-7.40 (7H, m), 7.47 (2H, d, J=8.0 Hz).

Example 212N-((1RS,2SR)-1-((4-fluorophenyl)methyl)-2-hydroxy-2-(4-(trifluoromethyl)phenyl)ethyl)-1-naphthalenecarboxamide

1) To a solution of 4-trifluoromethylacetophenone (57.8 g, 0.307 mol)and ethanol (1 ml) in ethyl carbonate (300 ml) was added sodium hydride(24.5 g, 60% in oil, 0.63 mol) by small portions. Because heat wasgenerated gradually, the reaction solution was ice-cooled and thereafterstirred at room temperature for 2 hrs. 6N Hydrochloric acid was addedthereto to stop the reaction. The mixture was diluted with water (300ml) and extracted with ethyl acetate (200 ml×2). The extract was washedwith water, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=50:1-5:1) to give ethyl3-oxo-3-(4-trifluoromethylphenyl)propionate (71.2 g, 89%).

IR ν max^(Neat)cm⁻¹: 1744, 1696, 1431, 1325, 1202, 1132, 1069, 1017,853. ¹H-NMR (CDCl₃)δ: 1.28 (3H×0.62, t, J=7.8 Hz, keto), 1.37 (3H×0.38,t, J=7.8 Hz, enol), 4.04 (2H×0.62, s, keto), 4.25 (2H,×0.62, q, J=7.8Hz, keto), 4.31 (2H,×0.38, q, J=7.8 Hz, enol), 5.75 (1H×0.38, s, enol),7.28 (1H×0.62, s, keto), 7.70 (2H×0.38, d, J=8.0 Hz, enol), 7.78(2H×0.62, d, J=8.0 Hz, keto), 7.90 (2H×0.38, d, J=8.0 Hz), 8.08(2H×0.62, d, J=8.0 Hz).

2) A mixture of ethyl 3-oxo-3-(4-trifluoromethylphenyl)propionate (38.2g, 0.147 mol), 4-fluorobenzyl bromide (25 g, 0.13 mol), potassiumcarbonate (36.6 g, 0.26 mol) and acetonitrile (500 ml) was stirred at60° C. for 3 hrs. The reaction solution was concentrated under reducedpressure, and water (500 ml) was added. The mixture was extracted withethyl acetate (500, 200 ml). The extract was washed with water, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=50:1-10:1, hexane:toluene=1:1) and crystallizedfrom cold hexane to give ethyl2-((4-fluorophenyl)methyl)-3-oxo-3-(4-(trifluoromethyl)phenyl)propionate(29.5 g, 55%).

mp 52-53° C. IR ν max^(KBr)cm⁻¹: 1723, 1692, 1514, 1323, 1231, 1130,1067, 853, 824. elemental analysis for C₁₉H₁₆F₄O₃ Calculated: C, 61.96;H, 4.38 Found: C, 61.97; H, 4.14. ¹H-NMR (CDCl₃)δ: 1.12 (3H, t, J=7.1Hz), 3.31 (2H, d, J=7.6 Hz), 4.10 (2H, q, J=7.1 Hz), 4.56 (1H, t, J=7.3Hz), 6.88-8.03 (2H, m), 7.12-7.32 (2H, m), 7.71 (2H, t, J=8.0 Hz), 8.04(2H, d, J=8.0 Hz)

3) To a solution of zinc chloride (21.54 g, 158 mmol) in ether (500 ml)was added sodium borohydride (11.96 g, 316 mmol), and the mixture wasstirred at room temperature for 30 min. Precipitated sodium chloride wasfiltered off. To the filtrate was gradually added a solution of ethyl2-((4-fluorophenyl)methyl)-3-oxo-3-(4-(trifluoromethyl)phenyl)propionate(28 g, 79 mmol) in ether (200 ml) under ice-cooling, and the mixture wasstirred at room temperature for 30 min. The reaction solution was pouredinto 1N aqueous hydrochloric acid solution (500 ml), and extracted withethyl acetate (500 ml×2). The extract was washed with saturated brine,dried over anhydrous magnesium sulfate and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1) to giveethyl(2RS,3RS)-2-((4-fluorophenyl)methyl)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)propionate(28 g, 100%) as a colorless oil.

IR ν max^(KBr)cm⁻1: 1713, 1510. Anal. Calcd for C₁₉H₁₈F₄O₃: C, 61.62; H,4.90 Found: C, 61.51; H, 4.87. ¹H-NMR (CDCl₃)δ: 0.95 (3H, t, J=7.4 Hz),2.80-3.06 (3H, m), 3.15 (1H, d, J=2.6 Hz), 3.91 (2H, q, J=7.4 Hz), 5.11(1H, brs), 6.84-7.06 (4H, m), 7.52 (2H, d, J=8.4 Hz), 7.63 (2H, d, J=8.4Hz).

4) To a solution ofethyl(2RS,3RS)-2-((4-fluorophenyl)methyl)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)propionate(27.5 g, 74.3 mmol) in methanol (300 ml) was added 1N aqueous sodiumhydroxide solution (150 ml, 150 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was poured into 1Naqueous hydrochloric acid solution (180 ml), and the mixture wasextracted with ethyl acetate (300 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. Recrystallization of the residue from ethylacetate-hexane gave(2RS,3RS)-2-((4-fluorophenyl)methyl)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)propionicacid (22.45 g, 88%).

mp 120-121° C. IR ν max^(KBr)cm⁻¹: 1713. Anal. Calcd for C₁₇H₁₄F₄O₃: C,59.65; H, 4.12 Found: C, 59.56; H, 4.03. ¹H-NMR (CDCl₃)δ: 2.90-3.10 (3H,m), 5.16 (1H, d, J=3.6 Hz), 6.82-7.12 (4H, m), 7.52 (2H, d, J=8.0 Hz),7.63 (2H, d, J=8.0 Hz).

5) To a solution of(2RS,3RS)-2-((4-fluorophenyl)methyl)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)propionicacid (21.0 g, 61.35 mmol) in tetrahydrofuran (500 ml) were addeddiphenylphosphoryl azide (14.5 ml, 67.5 mmol) and triethylamine (12.9ml, 92 mmol), and the mixture was heated under reflux for 3 hrs. Thereaction solution was diluted with water (500 ml), and the mixture wasextracted with ethyl acetate (500 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate). Recrystallization from ethylacetate-hexane gave(4RS,5SR)-4-((4-fluorophenyl)methyl)-5-(4-(trifluoromethyl)phenyl)-1,3-oxazolidin-2-one(19.24 g, 92%).

mp 160-161° C. IR ν max^(KBr)cm⁻¹: 1738, 1508. Anal. Calcd forC₁₇H₁₃F₄NO₂: C, 60.18; H, 3.86 ; N, 4.13. Found: C, 60.01; H, 3.99; N,4.06. ¹H-NMR (CDCl₃)δ: 2.10-2.34 (2H, m), 4.20-4.34 (1H, m), 5.11 (1H,s), 5.86 (1H, d, J=7.8 Hz), 6.97 (4H, d, J=9.0 Hz), 7.51 (2H, d, J=8.2Hz), 7.70 (2H, d, J=8.2 Hz).

6) To a solution of(4RS,5SR)-4-((4-fluorophenyl)methyl)-5-(4-(trifluoromethyl)phenyl)-1,3-oxazolidin-2-one(18 g, 53.1 mmol) in ethanol (300 ml) was added 8N aqueous sodiumhydroxide solution (19.9 ml, 159 mmol), and the mixture was heated underreflux for 4 hrs. The reaction solution was concentrated, diluted withwater (300 ml), and extracted with ethyl acetate (300 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. Recrystallization of the residuefrom ethyl acetate-hexane gave(1RS,2SR)-2-amino-3-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1-propanol(14.1 g, 85%).

mp 130-131° C. IR ν max^(KBr)cm⁻¹: 1618, 1601, 1588. Anal. Calcd forC₁₆H₁₅F₄NO: C, 61.34; H, 4.83; N, 4.47. Found: C, 61.23; H, 4.72; N,4.41. ¹H-NMR (CDCl₃)δ: 2.32 (1H, dd, J=14.0, 10.6 Hz), 2.68 (1H, dd,J=14.0, 3.4 Hz), 3.20-3.36 (1H, m), 4.76 (1H, d, J=4.4 Hz), 6.90-7.16(4H, m), 7.52 (2H, d, J=8.2 Hz), 7.65 (2H, d, J=8.2 Hz).

7) To a solution of(1RS,2SR)-2-amino-3-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added 1-naphthoylchloride (282 ml, 1.87 mmol) and saturated aqueous sodium hydrogencarbonate (15 ml), and the mixture was stirred at room temperature for 2hrs. The reaction solution was diluted with water (100 ml) and extractedwith ethyl acetate (100 ml×2). The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. Recrystallization of the residue from ethylacetate-hexane gave the title compound (614 mg, 91%).

mp 207-208° C. IR ν max^(KBr)cm⁻¹: 1640. Anal. Calcd for C₂₇H₂₁F₄NO₂: C,69.37; H, 4.53; N, 3.00. Found: C, 69.21; H, 4.46; N, 2.87. ¹H-NMR(CDCl₃)δ: 2.92 (1H, dd, J=14.2, 10.4 Hz), 3.13 (1H, dd, J=14.2, 4.0 Hz),3.39 (1H, s), 4.72-4.90 (1H, m), 5.13 (1H, s), 5.98 (1H, d, J=8.4 Hz),7.04-7.60 (12H, m), 7.70-7.92 (3H, m).

Example 2134-fluoro-N-((1RS,2SR)-1-((4-fluorophenyl)methyl)-2-hydroxy-2-(4-(trifluoromethyl)phenyl)ethyl)-1-naphthalenecarboxamide

To a solution of(1RS,2SR)-2-amino-3-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in acetonitrile (30 ml) were added4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg,1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol), and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate).Recrystallization from ethyl acetate-hexane gave the title compound (430mg, 62%).

mp 235-236° C. IR ν max^(KBr)cm⁻¹: 1651, 1605, 1510. Anal. Calcd forC₂₇H₂₀F₅NO₂: C, 66.80; H, 4.15; N, 2.89. Found: C, 66.59; H, 4.25; N,2.90. ¹H-NMR (CDCl₃)δ: 2.79 (1H, dd, J=14.2, 11.0 Hz), 2.98 (1H, dd,J=14.2, 4.4 Hz), 3.75 (1H, s), 4.70-4.88 (1H, m), 5.18-5.22 (1H, m),5.91 (1H, d, J=8.4 Hz), 6.92-7.10 (3H, m), 7.12-7.22 (3H, m), 7.40-7.80(7H, m), 8.10 (1H, d, J=8.4 Hz).

Example 214N-((1RS,2SR)-1-((4-fluorophenyl)methyl)-2-hydroxy-2-(4-(trifluoromethyl)phenyl)ethyl)cyclohexanecarboxamide

To a solution of(1RS,2SR)-2-amino-3-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in ethyl acetate (15 ml) were addedcyclohexanecarbonyl chloride (288 ml, 2.15 mmol) and saturated aqueoussodium hydrogen carbonate (15 ml), and the mixture was stirred at roomtemperature for 3 hrs. The reaction solution was diluted with water (100ml) and extracted with ethyl acetate (100 ml×2). The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. Recrystallization of the residue fromethyl acetate-hexane gave the title compound (550 mg, 90%).

mp 220-221° C. IR ν max^(KBr)cm⁻¹: 1645, 1510, 1329. Anal. Calcd forC₂₃H₂₅F₄NO₂: C, 65.24; H, 5.95; N, 3.31. Found: C, 65.07; H, 5.85; N,3.22. ¹H-NMR (CDCl₃)δ: 1.04-1.40 (5H, m), 1.50-1.80 (5H, m), 1.82-2.10(1H, m), 2.66 (1H, dd, J=14.4, 10.8 Hz), 2.83 (1H, dd, J=14.4, 4.6 Hz),4.34-4.50 (2H, m), 5.04 (1H, brs), 5.36 (1H, d, J=7.4 Hz), 6.90-7.12(4H, m), 7.52 (2H, d, J=8.0 Hz), 7.66 (2H, d, J=8.0 Hz).

Example 215N-((1RS,2SR)-1-((4-fluorophenyl)methyl)-2-hydroxy-2-(4-(trifluoromethyl)phenyl)ethyl)-4-phenylbutyramide

To a solution of(1RS,2SR)-2-amino-3-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1-propanol(450 mg, 1.44 mmol) in acetonitrile (30 ml) were added4-phenyl-n-butyric acid (236 mg, 1.44 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (358 mg,1.87 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol), and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate).Recrystallization from ethyl acetate-hexane gave the title compound (450mg, 68%).

mp 155-156° C. IR ν max^(KBr)cm⁻¹: 1645, 1537, 1510. Anal. Calcd forC₂₆H₂₅F₄NO₂: C, 67.96; H, 5.48; N, 3.05. Found: C, 67.98; H, 5.68; N,3.06. ¹H-NMR (CDCl₃)δ: 1.70-1.90 (2H, m), 2.00-2.20 (2H, m), 2.44-2.60(2H, m), 2.62-2.84 (2H, m), 4.10 (1H, d, J=4.0 Hz), 4.32-4.48 (1H, m),4.98-5.06 (1H, m), 5.40 (1H, d, J=7.6 Hz) 6.86-7.14 (6H, m), 7.16-7.34(3H, m), 7.51 (2H, d, J=8.0 Hz), 7.63 (2H, d, J=8.0 Hz).

Example 216N-[(1RS,2SR)-2-(4-chlorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1) ethyl3-(4-chlorophenyl)-3-oxo-2-[3-(1,1,2,2-tetrahydroethoxy)benzyl]propionate

To 3-(1,1,2,2-tetrahydroethoxy)toluene (7.43 ml, 44 mmol) in carbontetrachloride (30 ml) were added N-bromosuccinimide (7.83 g, 44 mmol)and 2,2′-azobisisobutyronitrile (0.2 g), and the mixture was heatedunder reflux for 30 min. After cooling the reaction solution, insolublematerial was removed, and the mixture was washed with diethyl ether. Thefiltrate was evaporated under reduced pressure to give3-(1,1,2,2-tetrahydroethoxy)-1-bromomethylbenzene. Ethyl3-(4-chlorophenyl)-3-oxopropionate (9.07 g, 40 mmol) was dissolved indimethoxyethane (100 ml). Sodium hydride (1.6 g, 60% in oil, 40 mmol)was added under ice-cooling, and the mixture was stirred for 1 hr.Thereto was dropwise added a solution of3-(1,1,2,2-tetrahydroethoxy)-1-bromomethylbenzene in dimethoxyethane (20ml) obtained above, and the mixture was stirred at room temperature for15 hrs. Water (100 ml) was added to the reaction solution, and themixture was extracted with ethyl acetate (100 ml×2). The extract waswashed with water, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gelchromatography (hexane:ethyl acetate=20:1-4:1) and crystallized fromhexane to give ethyl3-(4-chlorophenyl)-3-oxo-2-[3-(1,1,2,2-tetrahydroethoxy)benzyl]propionate(7.85 g, 45%).

mp 60-61° C. IR ν max^(KBr)cm⁻¹: 1723, 1684, 1590, 1325, 1275, 1231,1200, 1134, 1096. elemental analysis for C₂₀H₁₇ClF₄O₄ Calculated: C,55.50;H, 3.96 Found: C, 55.55;H, 3.83 ¹H-NMR (CDCl₃)δ: 1.12 (3H, t,J=7.2 Hz), 3.33 (2H, d, J=8.0 Hz), 4.10 (2H, q, J=7.2 Hz), 4.55 (1H, t,J=7.0 Hz), 5.89 (1H, tt, J=53.1 Hz, 2.2 Hz), 7.00-7.20 (3H, m),7.20-7.35 (1H, m), 7.42 (2H, d, J=8.0 Hz), 7.89 (2H, d, J=8.0 Hz).

2)ethyl(2RS,3RS)-3-(4-chlorophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrahydroethoxy)benzyl]propionate

To a suspension of anhydrous zinc chloride (4.09 g, 30 mmol) in diethylether (100 ml) was added sodium borohydride (2.53 g, 60 mmol) by smallportions, and the mixture was stirred for 2. hrs. Insoluble material wasfiltered off, and the mixture was washed with diethyl ether. Thefiltrate was ice-cooled, and a solution of ethyl3-(4-chlorophenyl)-3-oxo-2-[3-(1,1,2,2-tetrahydroethoxy)benzyl]propionate(6.5 g, 15 mmol) in diethyl ether (20 ml) was added thereto. After themixture was stirred at room temperature for 1 hr., it was cooled withice again, and the reaction was stopped by 1N hydrochloric acid. Theobtained mixture was extracted with ethyl acetate (100 ml×2). After themixture was washed with water, it was dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel chromatography (hexane:ethyl acetate=10:1-3:1) to giveethyl(2RS,3RS)-3-(4-chlorophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrahydroethoxy)benzyl]propionate(6.5 g, 99%) as a colorless oil.

IR ν max^(Neat)cm⁻¹: 1723, 1489, 1302, 1277, 1198, 1123, 1094. ¹H-NMR(CDCl₃)δ: 0.94 (3H, t, J 7.2 Hz), 2.90-3.10 (3H, m), 3.90 (2H, d, J=7.2Hz), 5.02 (1H, br), 5.88 (1H, tt, J=53.1 Hz, 2.3 Hz), 6.90-7.10 (3H, m),7.22 (1H, d, J=7.6 Hz), 7.27 (1H, d, J=3.4 Hz).

3)(2RS,3RS)-3-(4-chlorophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrahydroethoxy)benzyl]propionicacid

To a solution ofethyl(2RS,3RS)-3-(4-chlorophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrahydroethoxy)benzyl]propionate(6.45 g, 14.8 mmol) in methanol (30 ml) was added 2N aqueous sodiumhydroxide solution (14.8 ml, 29.6 mmol), and the mixture was stirred atroom temperature for 4 hrs. The reaction solution was acidified with 1Nhydrochloric acid (100 ml), and the mixture was extracted with ethylacetate (100 ml×2). After the extract was washed with water and driedover anhydrous magnesium sulfate, it was evaporated under reducedpressure. The residue was crystallized from hexane to give(2RS,3RS)-3-(4-chlorophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrahydroethoxy)benzyl]propionicacid (5.39 g, 89%).

mp 88-90° C. IR ν max^(KBr)cm⁻¹: 1694, 1489, 1277, 1206, 1127. elementalanalysis for C₁₈H₁₅ClF₄O₄, Calculated: C, 53.15;H, 3.72, Found: C,53.26;H, 3.87 ¹H-NMR (CDCl₃)δ: 2.80-3.10 (3H, m), 5.07 (1H, d, J=3.6Hz), 5.88 (1H, tt, J=53.1 Hz, 2.6 Hz), 6.90-7.15. (4H, m), 7.20-7.35(4H, m).

4)(4RS,5SR)-5-(4-chlorophenyl)-4-[3-(1,1,2,2-tetrahydroethoxy)benzyl]-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-(4-chlorophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrahydroethoxy)benzyl]propionicacid (5.39 g, 13.3 mmol) in tetrahydrofuran (100 ml) were addeddiphenylphosphoryl azide (3.70 ml, 17.2 mmol) and triethylamine (2.59ml, 18.6 mmol). The mixture was stirred at room temperature for 1 hr.and heated under reflux for 3 hrs. The reaction solution wasconcentrated under reduced pressure. Water (100 ml) was added and themixture was extracted with ethyl acetate (100 ml×2). The extract waswashed with water, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gelchromatography (hexane:ethyl acetate=2:1-1:1) and precipitated crystalswere filtered by adding hexane to give(4RS,5SR)-5-(4-chlorophenyl)-4-[3-(1,1,2,2-tetrahydroethoxy)benzyl]-1,3-oxazolidin-2-one(4.65 g, 87%).

mp 134-135° C. IR ν max^(KBr)cm⁻¹: 3243, 1740, 1489, 1447, 1343, 1273,1238, 1198, 1125, 1088. elemental analysis for C₁₈H₁₄ClF₄NO₃,Calculated: C, 53.55;H, 3.49;N, 3.47, Found: C, 53.56;H, 3.28;N, 3.48.¹H-NMR (CDCl₃)δ: 2.18-2.40 (2H, m), 4.20-4.35 (1H, m), 5.05 (1H, br s),5.79 (1H, d, J=8.0 Hz), 5.90 (1H, tt, J=54.8 Hz, 2.6 Hz), 6.85-7.00 (2H,m), 7.05-7.20 (1H, m), 7.20-7.50 (5H, m).

5)(1RS,2SR)-2-amino-1-(4-chlorophenyl)-3-[3-(1,1,2,2-tetrahydroethoxy)phenyl]-1-propanol

To a solution of(4RS,5SR)-5-(4-chlorophenyl)-4-[3-(1,1,2,2-tetrahydroethoxy)benzyl]-1,3-oxazolidin-2-one(4.35 g, 10.8 mmol) in ethanol (20 ml) was added 8N aqueous sodiumhydroxide solution (5.39 ml, 43.1 mmol), and the mixture was heatedunder reflux for 6 hrs. The reaction solution was concentrated underreduced pressure. Water (100 ml) was added, and the mixture wasextracted with ethyl acetate (100 ml×2). The extract was washed withwater, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was crystallized from the mixture ofhexane and diethyl ether to give(1RS,2SR)-2-amino-1-(4-chlorophenyl)-3-[3-(1,1,2,2-tetrahydroethoxy)phenyl]-1-propanol(3.61 g, 89%).

mp 96-97° C. IR ν max^(KBr)cm⁻¹: 1611, 1588, 1489, 1308, 1196, 1119.elemental analysis for C₁₇H₁₆ClF₄NO₂, Calculated: C, 54.05;H, 4.27;N,3.71, Found: C, 54.08;H, 4.34;N, 3.75. ¹H-NMR (CDCl₃)δ: 2.36 (1H, dd,J=13.6. Hz, 10.2 Hz), 2.77 (1H, dd, J=13.6 Hz, 3.2 Hz), 3.20-3.40 (1H,m), 4.66 (1H, d, J=4.6 Hz), 5.89 (1H, tt, J=53.0 Hz, 2.5 Hz), 6.99 (1H,s), 7.00-7.15 (2H, m), 7.20-7.40 (5H, m).

6)N-[(1RS,2SR)-2-(4-chlorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-chlorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(0.280 g, 0.741 mmol), 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylicacid (0.14 g, 0.74 mmol) and 1-hydroxybenzotriazole hydrate (0.11 g,0.74 mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.14 g,0.74 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance. white powder yield 0.373 g, 92%

mp 182-183° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 1.93-2.06 (2H, m), 2.15-2.24(2H, m), 2.67 (2H, t, J=6.1 Hz), 2.78 (1H, dd, J=10.9 Hz, 14.9 Hz), 2.98(1H, dd, J=4.2 Hz, 14.6 Hz), 3.71 (1H, d, J=3.6 Hz), 4.60-4.73 (1H, m),5.04 (1H, t, J=3.7 Hz), 5.74 (1H, d, J=8.4 Hz), 5.89 (1H, tt, J=2.7 Hz,53.0 Hz), 5.93 (1H, td, J=5.6 Hz, 11.0 Hz), 6.21 (1H, d, J=11.6 Hz),6.95-7.18 (6H, m), 7.31-7.43 (5H, m); IR (KBr) 3270, 2940, 1640, 1537,1198, 1125 cm⁻¹; Anal. Calcd for C₂₉H₂₆ClF₄NO₃: C, 63.56; H, 4.78; N,2.56. Found: C, 63.51; H, 4.69; N, 2.52.

Example 217N-((1RS,2SR)-2-hydroxy-2-(4-(phenyloxy)phenyl)-1-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1) To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (7.8 g, 37.5mmol) in carbon tetrachloride (80 ml) were added N-bromosuccinimide(7.33 g, 41.2 mmol) and 2,2′-azobis(isobutyronitrile) (300 mg, 1.87mmol), and the mixture was heated under reflux for 6 hrs. After cooling,the reaction solution was filtered, and the filtrate was concentrated toprepare ethyl 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To asolution of ethyl 3-(4-phenoxyphenyl)-3-oxopropionate (10.7 g, 37.5mmol) in 1,2-dimethoxyethane (120 ml) was added sodium hydride (60% inoil, 1.50 g, 37.5 mmol) under ice-cooling, and the mixture was stirredat room temperature for 30 min. To the reaction solution was dropwiseadded a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotolueneprepared earlier in 1,2-dimethoxyethane (10 ml), and the reactionsolution was stirred at room temperature for 1 hr. The reaction solutionwas poured into water (100 ml), and the mixture was extracted with ethylacetate (100 ml×2). The extract was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (toluene) to give ethyl3-oxo-3-(4-phenyloxyphenyl)-2-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionate(9.92 g, 54%) as a colorless oil.

¹H-NMR (CDCl₃)δ: 1.13 (3H, t, J=7.0 Hz), 3.33 (2H, d, J=6.8 Hz), 4.11(2H, q, J=7.0 Hz), 4.56 (1H, t, J=7.6 Hz), 5.88 (1H, tt, J=53.0, 2.8Hz), 6.90-7.48 (11H, m), 7.90-8.02 (2H, m).

IR ν max^(KBr)cm⁻¹: 1738, 1682, 1605, 1586, 1505, 1489, 1449, 1420.Anal. Calcd for C₂₆H₂₂F₄O₅.0.3H₂O: C, 62.98; H, 4.59 Found: C, 62.84; H,4.46.

2) To a solution of zinc chloride (5.34 g, 39.2 mmol) in diethyl ether(120 ml) was added sodium borohydride (2.97 g, 78.4 mmol), and themixture was stirred at room temperature for 30 min. Insoluble materialwas filtered off, and a solution of ethyl3-oxo-3-(4-phenyloxyphenyl)-2-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionate(9.61 g, 19.6 mmol) in diethyl ether (60 ml) was added to the filtrate.The mixture was stirred at room temperature for 30 min. 1N Hydrochloricacid was added to the reaction solution under ice-cooling to quench thereaction. Then, water (150 ml) was added and the mixture was extractedwith ethyl acetate (200 ml×2). The extract was washed with water andsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) to give ethyl(2RS,3RS)-3-hydroxy-3-(4-(phenyloxy)phenyl)-2-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionate(6.50 g, 67%) as a colorless oil.

¹H-NMR (CDCl₃)δ: 0.94 (3H, t, J=7.0 Hz), 2.90-3.10 (4H, m), 3.89 (2H, q,J=7.0 Hz), 4.98-5.06 (1H, m), 5.89 (1H, tt, J=53.0, 2.8 Hz), 6.92-7.42(13H, m). IR ν max^(KBr)cm⁻¹: 1725, 1611, 1590, 1507, 1489, 1449. Anal.Calcd for C₂₆H₂₄F₄O₅: C, 63.41; H, 4.91 Found: C, 63.32; H, 4.97.

3) To a solution ofethyl(2RS,3RS)-3-hydroxy-3-(4-(phenyloxy)phenyl)-2-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionate(6.14 g, 12.5 mmol) in methanol (30 ml) was added 2N aqueous sodiumhydroxide solution (12.5 ml, 25.0 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure.Recrystallization of the residue from ethyl acetate-hexane gave(2RS,3RS)-3-hydroxy-3-(4-(phenyloxy)phenyl)-2-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionicacid (4.51 g, 89%).

¹H-NMR (CDCl₃)δ: 2.94-3.10 (3H, m), 5.07 (1H, d, J=4.2 Hz), 5.87 (1H, t,J=53.0, 3.0 Hz), 6.92-7.40 (13H, m). IR ν max^(KBr)cm⁻¹: 1711, 1613,1590, 1508, 1489. mp 109-110° C. Anal. Calcd for C₂₄H₂₀F₄O₅: C, 62.07;H, 4.34 Found: C, 62.09; H, 4.42.

4) To a solution of(2RS,3RS)-3-hydroxy-3-(4-(phenyloxy)phenyl)-2-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionicacid (4.3 g, 10.6 mmol) in tetrahydrofuran (80 ml) were addeddiphenylphosphoryl azide (2.52 ml, 11.7 mmol) and triethylamine (2.23ml, 16.0 mmol), and the mixture was heated under reflux for 2 hrs. Thereaction solution was allowed to cool and water (200 ml) was added. Themixture was extracted with ethyl acetate (100 ml×2). The extract waswashed successively with 1N hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=10:1-1:1).Recrystallization from ethyl acetate-hexane gave(4RS,5SR)-5-(4-(phenyloxy)phenyl)-4-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)-1,3-oxazolidin-2-one(3.92 g, 80%).

¹H-NMR (CDCl₃)δ: 2.24-2.44 (2H, m), 4.18-4.32 (1H, m), 5.08 (1H, brs),5.79 (1H, d, J=8.0 Hz), 5.90 (1H, tt, J=53.0, 3.0 Hz), 6.86-7.20 (8H,m), 7.22-7.42 (5H, m). IR ν max^(KBr)cm⁻¹: 1759, 1612, 1590, 1508, 1489.mp 90-91° C. Anal. Calcd for C₂₄H₁₉F₄NO₄: C, 62.47; H, 4.15; N, 3.04.Found: C, 62.54; H, 4.05; N, 3.04.

5) To a solution of(4RS,5SR)-5-(4-(phenyloxy)phenyl)-4-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)-1,3-oxazolidin-2-one(3.7 g, 8.02 mmol) in ethanol (10 ml) was added 8N aqueous sodiumhydroxide solution (5.0 ml, 40 mmol), and the mixture was heated underreflux for 4 hrs. The reaction solution was concentrated, diluted withwater (100 ml) and extracted with ethyl acetate (100 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. Recrystallization of the residuefrom ethyl acetate-hexane gave(1RS,2SR)-2-amino-1-(4-(phenyloxy)phenyl)-3-(3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)-1-propanol(3.05 g, 87%).

¹H-NMR (CDCl₃)δ: 1.20-2.00 (2H, br), 2.41 (1H, dd, J=13.8, 10.2 Hz),2.88 (1H, dd, J=13.8, 3.2 Hz), 3.22-3.38 (1H, m), 4.65 (1H, d, J=5.2Hz), 5.89 (1H, tt, J=53.0, 3.0 Hz), 6.98-7.18 (8H, m), 7.28-7.42 (5H,m). IR ν max^(KBr)cm⁻¹: 1611, 1590, 1507, 1489, 1449. mp 85-86° C. Anal.Calcd for C₂₃H₂₁F₄NO₃: C, 63.44; H, 4.86; N, 3.22. Found: C, 63.44; H,4.76; N, 3.22.

6) To a solution of(1RS,2SR)-2-amino-1-(4-(phenyloxy)phenyl)-3-(3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)-1-propanol(300 mg, 0.69 mmol) in acetonitrile (16 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (130 mg, 0.69mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198mg, 1.03 mmol) and 1-hydroxy-1H-benzotriazole (106 mg, 0.69 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with 1Nhydrochloric acid, 1N aqueous sodium hydroxide solution and saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. Recrystallization of the residue from ethylacetate-hexane gave the title compound (285 mg, 68%).

¹H-NMR (CDCl₃)δ: 1.90-2.10 (2H, m), 2.12-2.28 (2H, m), 2.60-2.72 (2H,m), 2.8 (1H, dd, J=14.8, 10.4 Hz), 3.04 (1H, dd, J=14.8, 4.0 Hz), 3.53(1H, s), 4.60-4.80 (1H, m), 5.02 (1H, s), 5.75 (1H, d, J=8.4 Hz), 5.89(1H, tt, J=53.0, 2.8 Hz), 5.90-6.00 (1H, m), 6.23 (1H, d, J=11.8 Hz),6.90-7.20 (12H, m), 7.22-7.48 (4H, m). IR ν max^(KBr)cm⁻¹: 1640, 1590,1507, 1489, 1449. mp 95-96° C.

Example 218N-((1RS,2SR)-2-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-2-hydroxy-1-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1) To a solution of 4-fluoroacetophenone (13.8 g, 100 mmol) inN,N-dimethylacetamide (100 ml) were added 4-chloro-3-ethylphenol (15.6g, 100 mmol) and potassium carbonate (16.6 g, 120 mmol), and the mixturewas heated under reflux for 10 hrs. The reaction solution wasconcentrated, diluted with water (300 ml) and extracted with ethylacetate (300 ml×2). The extract was washed successively with water andsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=10:1) to give4-((4-chloro-3-ethylphenyl)oxy)acetophenone (24.2 g, 88%) as a colorlessoil.

¹H-NMR (CDCl₃)δ: 1.22 (3H, t, J=7.4 Hz), 2.58 (3H, s), 2.74 (2H, q,J=7.4 Hz), 6.84 (1H, dd, J=8.8, 3.0 Hz), 6.94-7.04 (3H, m), 7.34 (1H, d,J=8.8 Hz), 7.90-8.00 (2H, m). IR ν max^(KBr)cm⁻¹: 1682, 1595, 1574,1503, 1472. Anal. Calcd for C₁₆H₁₅ClO₂: C, 69.95; H, 5.50 Found: C,69.93; H, 5.65

2) To a solution of 4-((4-chloro-3-ethylphenyl)oxy)acetophenone (24.2 g,88.2 mmol) in diethyl carbonate (100 ml) were added ethanol (0.3 mI) andsodium hydride (60% in oil, 7.06 g, 176 mmol) under ice-cooling, and themixture was stirred at room temperature for 2 hrs.

6N Hydrochloric acid was added to the reaction solution to quench thereaction. Water (300 ml) was added, and the mixture was extracted withethyl acetate (300 ml×2). The extract was washed successively with waterand saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=50:1-5:1) to give ethyl3-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-oxopropionate (29.3 g, 96%)as a brown oil.

¹H-NMR (CDCl₃)δ: 1.08-1.20 (6H, m), 2.68-2.82 (2H, m), 3.95 (2H×7/8, s),4.14-4.30 (2H, m), 5.60 (1H×1/8, s), 6.80-6.90 (1H, m), 6.92-7.04 (3H,m), 7.32 (1H×1/8, d, J=8.4 Hz), 7.35 (1H×7/8, d, J=8.4 Hz), 7.75(2H×1/8, d, J=9.2 Hz), 7.93 (2H×7/8, d, J=9.2 Hz). IR ν max^(KBr)cm⁻¹:1744, 1682, 1595, 1576, 1505, 1472, 1410. Anal. Calcd for C₁₉H₁₉F₅ClO₄:C, 65.80; H, 5.52 Found: C, 65.98; H, 5.53.

3) To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (6.0 g, 28.8mmol) in carbon tetrachloride (60 ml) were added N-bromosuccinimide(5.65 g, 31.7 mmol) and 2,2′-azobis(isobutyronitrile) (237 mg, 1.44mmol), and the mixture was heated under reflux for 6 hrs. After cooling,the reaction solution was filtered, and the filtrate was concentrated togive 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution ofethyl 3-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-oxopropionate (10 g,28.8 mmol) in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60%in oil, 1.15 g, 28.8 mmol) under ice-cooling, and the mixture wasstirred at room temperature for 30 min. To the reaction solution wasdropwise added a solution of3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in1,2-dimethoxyethane (10 ml), and the reaction solution was stirred atroom temperature for 1 hr. The reaction solution was poured into water(100 ml), and the mixture was extracted with ethyl acetate (100 ml×2).The extract was washed with water and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (toluene) togive ethyl3-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-oxo-2-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionate(9.26 g, 58%) as a colorless oil.

¹H-NMR (CDCl₃)δ: 1.13 (3H, t, J=7.0 Hz), 1.22 (3H, t, J=7.6 Hz), 2.74(2H, q, J=7.6 Hz), 3.33 (2H, d, J=7.2 Hz), 4.11 (2H, q, J=7.0 Hz), 4.56(1H, t, J=7.2 Hz), 5.88 (1H, tt, J=53.2, 2.8 Hz), 6.83 (1H, dd, J=8.6,3.0 Hz), 6.90-7.38 (8H, m), 7.90-8.00 (2H, m). IR ν max^(KBr)cm⁻¹: 1738,1682, 1595, 1576, 1505, 1472. Anal. Calcd for C₂₈H₂₅ClF₄O₅: C, 60.82; H,4.56 Found: C, 60.79; H, 4.38.

4) To a solution of zinc chloride (4.44 g, 32.6 mmol) in diethyl ether(100 ml) was added sodium borohydride (2.46 g, 65.1. mmol), and themixture was stirred at room temperature for 30 min. Insoluble materialwas filtered off, a solution of ethyl3-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-oxo-2-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionate(9.0 g, 16.3 mmol) in diethyl ether (50 ml) was added to the filtrate,and the mixture was stirred at room temperature for 30 min. 1NHydrochloric acid was added to the reaction solution under ice-coolingto quench the reaction. Then, water (150 ml) was added and the mixturewas extracted with ethyl acetate (200 ml×2). The extract was washed withwater and saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1) to give ethyl(2RS,3RS)-3-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-hydroxy-2-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionate(6.79 g, 75%) as a colorless oil.

¹H-NMR (CDCl₃)δ: 0.95 (3H, t, J=7.0 Hz), 1.21 (3H, t, J=7.6 Hz), 2.72(2H, q, J=7.6 Hz), 2.90-3.10 (4H, m), 3.90 (2H, q, J=7.0 Hz), 4.93 (1H,brs), 5.89 (1H, tt, J=53.0, 3.0 Hz.), 6.76 (1H, dd, J=8.8, 3.0 Hz),6.82-7.10 (6H, m), 7.20-7.42 (4H, m). IR ν max^(KBr)cm⁻¹: 1726, 1611,1588, 1507, 1474. Anal. Calcd for C₂₈H₂₇ClF₄O₅: C, 60.60; H, 4.90 Found:C, 60.53; H, 4.90.

5) To a solution ofethyl(2RS,3RS)-3-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-hydroxy-2-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionate(6.6 g, 11.9 mmol) in methanol (30 ml) was added 2N aqueous sodiumhydroxide solution (11.9 ml, 23.8 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from hexane to give(2RS,3RS)-3-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-hydroxy-2-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionicacid (5.28 g, 84%).

¹H-NMR (CDCl₃)δ: 1.21 (3H, t, J=7.6 Hz), 2.71 (2H, q, J=7.6 Hz),2.92-3.10 (3H, m), 5.07 (1H, d, J=4.0 Hz), 5.87 (1H, tt, J=53.0, 3.0Hz), 6.75 (1H, dd, J=8.4, 3.0 Hz), 6.88-7.10 (6H, m), 7.20-7.40 (4H, m).IR ν max^(KBr)cm⁻¹: 1713, 1611, 1599, 1507, 1472. mp 75-76° C. Anal.Calcd for C₂₆H₂₃ClF₄O₅: C, 59.27; H, 4.40 Found: C, 59.22; H, 4.43.

6) To a solution of(2RS,3RS)-3-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-hydroxy-2-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionicacid (5.18 g, 9.83 mmol) in tetrahydrofuran (75 ml) were addeddiphenylphosphoryl azide (2.33 ml, 10.8 mmol) and triethylamine (2.06ml, 14.8 mmol), and the mixture was heated under reflux for 2 hrs. Thereaction solution was allowed to cool and water (200 ml) was added. Themixture was extracted with ethyl acetate (100 ml×2). The extract waswashed successively with 1N hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate). Recrystallizationfrom ethyl acetate-hexane gave(4RS,5SR)-5-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-4-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)-1,3-oxazolidin-2-one(4.56 g, 89%).

¹H-NMR (CDCl₃)δ: 1.22 (3H, t, J=7.6 Hz), 2.20-2.44 (2H, m), 2.73 (2H, q,J=7.6 Hz), 4.18-4.32 (1H, m), 4.98 (1H, s), 5.80 (1H, d, J=7.8 Hz), 5.90(1H, tt, J=53.0, 3.0 Hz), 6.80 (1H, dd, J=8.4, 3.0 Hz), 6.88-7.20 (5H,m), 7.22-7.44 (5H, m). IR ν max^(KBr)cm⁻¹: 1759, 1612, 1588, 1508, 1472.mp 100-101° C. Anal. Calcd for C₂₆H₂₂ClF₄NO₄: C, 59.61; H, 4.23; N,2.67. Found: C, 59.67; H, 4.27; N, 2.76.

7) To a solution of(4RS,5SR)-5-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-4-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)-1,3-oxazolidin-2-one(4.3 g, 8.21 mmol) in ethanol (20 ml) was added 8N aqueous sodiumhydroxide solution (5.13 ml, 41.1 mmol), and the mixture was heatedunder reflux for 4 hrs. The reaction solution was concentrated, dilutedwith water (100 ml), and extracted with ethyl acetate (100 ml×2). Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure to give(1RS,2SR)-2-amino-1-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-(3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)-1-propanol(3.64 g, 89%) as a colorless oil.

¹H-NMR (CDCl₃)δ: 1.21 (3H, t, J=7.6 Hz), 2.41 (1H, dd, J=13.6, 10.2 Hz),2.72 (2H, q, J=7.6 Hz), 2.87 (1H, dd, J=13.6, 3.2 Hz), 4.65 (1H, d,J=5.2 Hz), 5.90 (1H, tt, J=53.0, 3.0 Hz), 6.78 (1H, dd, J=8.4, 3.0 Hz),6.88-7.18 (6H, m), 7.28-7.40 (4H, m). IR ν max^(KBr)cm⁻¹: 1611, 1586,1505, 1472, 1412. Anal. Calcd for C₂₅H₂₄ClF₄NO₃: C, 60.31; H, 4.86; N,32.81 Found: C, 60.31; H, 5.18; N, 2.85.

8) To a solution of(1RS,2SR)-2-amino-1-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-(3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)-1-propanol(300 mg, 0.60 mmol) in acetonitrile (16 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (114 mg, 0.60mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (174mg, 0.91 mmol) and 1-hydroxy-1H-benzotriazole (92 mg, 0.60 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with 1Nhydrochloric acid, 1N aqueous sodium hydroxide solution and saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. Recrystallization of the residue from ethylacetate-hexane gave the title compound (318 mg, 79%).

¹H-NMR (CDCl₃)δ: 1.20 (3H, t, J=7.2 Hz), 1.90-2.08 (2H, m), 2.10-2.26(2H, m), 2.60-2.84 (5H, m), 3.02 (1H, dd, J=14.6, 4.0 Hz), 3.50-3.90(1H, br), 4.60-4.78 (1H, m), 5.01 (1H, d, J=3.6 Hz), 5.60-6.22 (4H, m),6.77 (1H, dd, J=8.8, 3.0 Hz), 6.84-7.20 (9H, m), 7.28 (2H, d, J=7.8 Hz),7.41 (2H, d, J=8.8 Hz). IR ν max^(KBr)cm⁻¹: 1613, 1588, 1505, 1472,1453. mp 116-117° C. Anal. Calcd for C₃₇H₃₄ClF₄NO₄: C, 66.51; H, 5.13;N, 2.10. Found: C, 66.22; H, 5.24; N, 2.25.

Example 2191,1-dimethylethyl(1RS,2SR)-2-(2-fluoropyridin-4-yl)-2-hydroxy-1-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethylcarbamate

1) To a solution of 2-amino-4-methylpyridine (100 g, 925 mmol) in 42%tetrafluoroboric acid (400 ml) was gradually added a solution of sodiumnitrite (64 g, 927 mmol) in water (100 ml) while cooling with dryice-acetone so that the inside temperature would not exceed 10° C. Thereaction solution was stirred at 45° C. for 30 min., 8N aqueous sodiumhydroxide solution (100 ml) was gradually added, and the mixture wasextracted with diethyl ether (300 ml×2). The extract was concentratedunder reduced pressure, and the residue was distilled away to give2-fluoro-4-methylpyridine (48 g). A solution of potassium permanganate(100 g, 632 mmol) in water (1.2 L) was heated to 80° C. and2-fluoro-4-methylpyridine (48 g) was added. The mixture was heated underreflux for 1 hr. Insoluble material was filtered off with celite fromthe reaction solution. The filtrate was concentrated to 200 ml, and 6Nhydrochloric acid was added until the pH became about 3. Theprecipitated crystals were collected by filtration to give2-fluoro-4-pyridinecarboxylic acid 2(19.8 g, 32%).

¹H-NMR (CDCl₃)δ: 7.50 (1H, s), 7.75 (1H, d, J=5.0 Hz), 8.40 (1H, d,J=5.0 Hz). IR ν max^(KBr)cm⁻¹: 3100, 1730, 1620. mp 258-260° C. Anal.Calcd for C₆H₄FNO₂: C, 51.07; H, 2.86; N, 9.93. Found: C, 50.77; H,2.80; N, 10.04.

2) To a solution of 2-fluoro-4-pyridinecarboxylic acid (10 g, 70.9 mmol)in tetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole(12.7 g, 78.0 mmol), and the mixture was heated under reflux for 30 min.The reaction solution was cooled and monoethyl malonate magnesium salt(11.2 g, 39.0 mmol) was added. The mixture was stirred at roomtemperature for 30 min. 1N Hydrochloric acid (200 ml) was added to thereaction solution, and the mixture was extracted with ethyl acetate (200ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=4:1)and recrystallized from hexane to give ethyl3-(2-fluoro-4-pyridyl)-3-oxopropionate (7.32 g, 49%).

¹H-NMR (CDCl₃)δ: 1.20-1.40 (3H, m), 3.98 (2H×1/5, s), 4.18-4.40 (2H, m),5.76 (1H×4/5, s), 7.26 (1H×4/5, s), 7.40 (1H×1/5, s), 7.50 (1H×4/5, d,J=7.4 Hz), 7.63 (1H×1/5, d, J=7.4 Hz), 8.32 (1H×4/5, d, J=7.0 Hz),8.43-(1H×1/5, d, J=7.0 Hz), 12.44 (1H×4/5, s). IR ν max^(KBr)cm⁻¹: 1744,1705, 1651, 1607, 1563. mp 66-67° C. Anal. Calcd for C₁₀H₁₀FNO₃: C,56.87; H, 4.77; N, 6.63. Found: C, 56.92; H, 4.69; N, 6.82.

3) To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (3.80 g, 18.2mmol) in carbon tetrachloride (50 ml) were added N-bromosuccinimide(3.54 g, 19.9 mmol) and 2,2′-azobis(isobutyronitrile) (136 mg, 0.83mmol), and the mixture was heated under reflux for 4 hrs. After cooling,the reaction solution was filtered, and the filtrate was concentrated togive ethyl 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solutionof ethyl 3-(2-fluoropyridin-4-yl)-3-oxopropionate (3.5 g, 16.6 mmol) in1,2-dimethoxyethane (35 ml) was added sodium hydride (60% in oil, 0.66g, 16.6 mmol) under ice-cooling, and the mixture was stirred at roomtemperature for 30 min. To the reaction solution was dropwise added asolution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene preparedearlier in 1,2-dimethoxyethane (5 ml), and the mixture was stirred atroom temperature for 1 hr. The reaction solution was poured into water(100 ml), and the mixture was extracted with ethyl acetate (100 ml×2).The extract was washed with water and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography(toluene:hexane=1:1) to give ethyl3-(2-fluoropyridin-4-yl)-3-oxo-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate(4.78 g, 69%) as a colorless oil.

¹H-NMR (CDCl₃)δ: 1.14 (3H, t, J=7.0 Hz), 3.35 (2H, d, J=7.4 Hz), 4.13(2H, q, J=7.0 Hz), 4.44-4.56 (1H, m), 5.90 (1H, tt, J=53.0, 3.0 Hz),7.00-7.38 (5H, m). IR ν max^(KBr)cm⁻¹: 1740, 1703, 1607, 1588, 1566.Anal. Calcd for C₁₉H₁₆F₅NO₄: C, 54.68; H, 3.86; N, 3.36. Found: C,54.44; H, 3.76; N, 3.55.

4) To a solution of zinc chloride (3.12 g, 22.9 mmol) in diethyl ether(100 ml) was added sodium borohydride (1.74 g, 45.8 mmol), and themixture was stirred at room temperature for 30 min. Insoluble materialwas filtered off, and a solution of ethyl3-(2-fluoropyridin-4-yl)-3-oxo-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate(4.78 g, 11.5 mmol) in diethyl ether (30 ml) was added to the filtrate.The mixture was stirred at room temperature for 30 min. 1N Hydrochloricacid was added to the reaction solution under ice-cooling to quench thereaction. Then, water (100 ml) was added and the mixture was extractedwith ethyl acetate (200 ml×2). The extract was washed with water andsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) to give ethyl3-(2-fluoropyridin-4-yl)-3-hydroxy-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate((2RS,3RS)form: (2RS,3SR) form=9:1, 4.05 g, 84%) as a colorless oil.

¹H-NMR (CDCl₃)δ: 0.92-1.06 (3H, m), 2.70-3.10 (3H, m), 3.54 (1H, dd,J=2.6 Hz), 3.90-4.04 (2H, m), 4.77 (1H×1/10, dd, J=8.8, 3.4 Hz), 5.13(1H×9/10, s), 5.89 (1H, tt, J=53.0, 3.0 Hz), 6.90-7.30 (7H, m),8.16-8.24 (1H, m). IR ν max^(KBr)cm⁻¹: 1728, 1615, 1588, 1572, 1487.Anal. Calcd for C₁₉H₁₈F₅NO₄: C, 54.42; H, 4.33; N, 3.34. Found: C,54.37; H, 4.39; N, 3.35.

5) To a solution ofethyl(2RS,3RS)-3-(2-fluoropyridin-4-yl)-3-hydroxy-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate(3.8 g, 9.06 mmol, (2RS,3RS) form: (2RS,3SR) form=9:1) in methanol (20ml) was added 2N aqueous sodium hydroxide solution (9.1 ml), 18.2 mmol),and the mixture was stirred at room temperature for 2 hrs. The reactionsolution was acidified with 1N hydrochloric acid and extracted withethyl acetate (200 ml×2). The extract was washed with water andsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. Recrystallization of the residue from ethylacetate-hexane gave(2RS,3RS)-3-(2-fluoropyridin-4-yl)-3-hydroxy-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionicacid (2.14 g, 60%).

¹H-NMR (CDCl₃)δ: 2.74-2.92, (1H, m), 2.98-3.16 (2H, m), 5.18 (1H, d,J=3.2 Hz), 5.88 (1H, tt, J=53.0, 3.0 Hz), 6.90-7.10 (4H, m), 7.16-7.30(2H, m), 8.17 (1H, d, J=5.2 Hz). IR ν max^(KBr)cm⁻¹: 1717, 1615, 1588,1570. mp 134-135° C. Anal. Calcd for C₁₇H₁₄F₅NO₄: C, 52.18; H, 3.61; N,3.58. Found: C, 52.20; H, 3.51; N, 3.58.

6) To a solution of(2RS,3RS)-3-(2-fluoropyridin-4-yl)-3-hydroxy-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionicacid (2.0 g, 5.11 mmol) in tetrahydrofuran (50 ml) were addeddiphenylphosphoryl azide (1.21 ml, 5.62 mmol) and triethylamine (1.07ml, 7.67 mmol), and the mixture was heated under reflux for 2 hrs. Thereaction solution was allowed to cool and water (200 ml) was added. Themixture was extracted with ethyl acetate (100 ml×2). The extract waswashed successively with 1N hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=1:1).Recrystallization from ethyl acetate-hexane gave(4RS,5SR)-5-(2-fluoropyridin-4-yl)-4-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidin-2-one(1.36 g, 69%).

¹H-NMR (CDCl₃)δ: 2.27 (1H, dd, J=14.0, 10.2 Hz), 2.41 (1H, dd, J=14.0,4.4 Hz), 4.28-4.42 (1H, m), 5.49 (1H, s), 5.81 (1H, d, J=8.0 Hz), 5.91(1H, tt, J=53.0, 2.6 Hz), 6.90-7.40 (6H, m), 8.30 (1H, d, J=5.2 Hz). IRν max^(KBr)cm⁻¹: 1771, 1615, 1588, 1574, 1489. mp 118-119° C. Anal.Calcd for C₁₇H₁₃F₅N₂O₃: C, 52.59; H, 3.37; N, 7.21. Found: C, 52.70; H,3.20; N, 7.20.

7) To a solution of(4RS,5SR)-5-(2-fluoropyridin-4-yl)-4-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidin-2-one(1.25 g, 3.22 mmol) in acetonitrile (20 ml) were added di-t-butyldicarbonate (0.84 g, 3.86 mmol) and dimethylaminopyridine (39 mg, 0.32mmol), and the mixture was stirred at room temperature for 2 hrs. Water(50 ml) was added to the reaction solution and the mixture was extractedwith ethyl acetate (50 ml×2). The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) and recrystallized from ethylacetate-hexane to give1,1-dimethylethyl(4RS,5SR)-5-(2-fluoropyridin-4-yl)-2-oxo-4-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidine-3-carboxylate(1.41 g, 89%).

¹H-NMR (CDCl₃)δ: 1.51 (9H, s), 2.60 (1H, dd, J=14.2, 8.8 Hz), 2.95 (1H,dd, J=14.2, 4.6 Hz), 4.82-4.98 (1H, m), 5.67 (1H, d, J=7.0 Hz), 5.90(1H, tt, J=53.0, 3.0 Hz), 6.54 (1H, d, J=7.4 Hz), 6.73 (1H, s), 6.82(1H, s), 6.94 (1H, d, J=5.0 Hz), 6.98-7.20 (2H, m), 8.09 (1H, d, J=5.2Hz). IR ν max^(KBr)cm⁻¹: 1821, 1726, 1615, 1588, 1574, 1489, 1416. mp113-114° C. Anal. Calcd for C₂₂H₂₁F₅N₂O₅: C, 54.10; H, 4.33; N, 5.74.Found: C, 54.10; H, 4.21; N, 5.72.

8) To a solution of1,1-dimethylethyl(4RS,5SR)-5-(2-fluoropyridin-4-yl)-2-oxo-4-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidine-3-carboxylate(1.30 g, 2.66 mmol) in methanol (7 ml) was added a solution (6.39 ml,3.19 mmol) of 0.5N sodium hydroxide in methanol, and the mixture wasstirred at room temperature for 10 min. To the reaction solution wasadded water (50 ml), and the mixture was extracted with ethyl acetate(50 ml×2). The extract was washed with saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to give the titlecompound (1.08 g, 88%).

¹H-NMR (CDCl₃)δ: 1.37 (9H, s), 2.60-2.80 (2H, m), 3.82-4.10 (2H, m),4.68 (1H, d, J=8.0 Hz), 5.01 (1H, s), 5.89 (1H, tt, J=53.0, 3.0 Hz),6.92-7.12 (4H, m), 7.18-7.32 (2H, m), 8.20 (1H, d, J=5.0 Hz). IR νmax^(KBr)cm⁻¹: 1752, 1694, 1615, 1570, 1512, 1489, 1449, 1412. mp143-144° C. Anal. Calcd for C₂₁H₂₃F₅N₂O₄: C, 54.55; H, 5.01; N, 6.06.Found: C, 54.32; H, 4.86; N, 6.07.

Example 220N-((1RS,2SR)-2-(2-fluoropyridin-4-yl)-2-hydroxy-1-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1) Trifluoroacetic acid (10 ml) was added to 1,1-dimethylethyl(1RS,2SR)-2-(2-fluoropyridin-4-yl)-2-hydroxy-1-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethylcarbamate(0.8 g, 1.73 mmol), and the mixture was stirred at room temperature for10 min. The reaction solution was concentrated under reduced pressure,1N aqueous sodium hydroxide solution (10 ml) was added, and the mixturewas extracted with ethyl acetate (20 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. Recrystallization of the residue from ethylacetate-hexane gave(1RS,2SR)-2-amino-1-(2-fluoropyridin-4-yl)-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol(0.59 g, 93%).

¹H-NMR (CDCl₃)δ: 2.40 (1H, dd, J=13.6, 10.6 Hz), 2.63 (1H, dd, J=13.6,3.2 Hz), 3.32-3.48 (1H, m), 4.79 (1H, d, J=4.0 Hz), 5.92 (1H, tt,J=53.0, 3.0 Hz), 6.92-7.40 (6H, m), 8.24 (1H, d, J=5.2 Hz). IR νmax^(KBr)cm⁻¹: 1613, 1588, 1568, 1487, 1449, 1410. mp 119-120° C. Anal.Calcd for C₁₆H₁₅F₅N₂O₂: C, 53.04; H, 4.17; N, 7.73. Found: C, 52.91; H,4.08; N, 7.60.

2) To a solution of(1RS,2SR)-2-amino-1-(2-fluoropyridin-4-yl)-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol(300 mg, 0.83 mmol) in acetonitrile (20 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (156 mg, 0.83mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (238mg, 1.24 mmol) and 1-hydroxy-1H-benzotriazole (127 mg, 0.83 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with 1Nhydrochloric acid, 1N aqueous sodium hydroxide solution and saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. Recrystallization of the residue from ethylacetate-hexane gave the title compound (347 mg, 79%).

¹H-NMR (CDCl₃)δ: 1.90-2.08 (2H, m), 2.10-2.26 (2H, m), 2.60-2.72 (2H,m), 2.80-2.92 (2H, m), 4.40-4.70 (2H, m), 5.11 (1H, d, J=2.6 Hz), 5.89(1H, tt, J=53.0, 3.0 Hz), 5.90-6.10 (2H, m), 6.24 (1H, d, J=11.6 Hz),6.92-7.38 (9H, m), 8.08 (1H, d, J=5.2 Hz). IR ν max^(KBr)cm⁻¹: 1636,1615, 1588, 1570, 1516, 1449, 1412. mp 159-160° C. Anal. Calcd forC₂₈H₂₅F₅N₂O₃.0.2H₂O: C, 62.73; H, 4.78; N, 5.23. Found: C, 62.64; H,4.80; N, 5.37.

Example 2211,1-dimethylethyl(1RS,2RS)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethylcarbamate

1) To a solution of 2-amino-6-methylpyridine (75 g, 693 mmol) in 42%tetrafluoroboric acid (291 ml) was gradually added a solution of sodiumnitrite (47.8 g, 693 mmol) in water (100 ml) while cooling with dryice-acetone so that the inside temperature would not exceed 10° C. Afterthe reaction solution was stirred at 45° C. for 30 min., 8N aqueoussodium hydroxide solution (100 ml) was gradually added, and the mixturewas extracted with diethyl ether (300 ml×2). The extract wasconcentrated under reduced pressure, and the residue was distilled awayto give 2-fluoro-6-methylpyridine (27.9 g). A solution of potassiumpermanganate (100 g, 632 mmol) in water (1.2 L) was heated to 80° C.,and 2-fluoro-6-methylpyridine (27.9 g) was added. The mixture was heatedunder reflux for 4 hrs. Insoluble material was filtered off with celitefrom the reaction solution, and the filtrate was concentrated to 200 ml.Then, 6N hydrochloric acid was added until the pH became about 3. Theprecipitated crystals were collected by filtration to give6-fluoro-2-pyridinecarboxylic acid (5.84 g, 14%).

¹H-NMR (CDCl₃)δ: 7.26 (1H, d, J=7.2 Hz), 7.36 (1H, s), 8.00-8.30 (1H,m). IR ν max^(KBr)cm⁻¹: 3100, 1730, 1620. mp 248-250° C. Anal. Calcd forC₆H₄FNO₂: C, 51.07; H, 2.86; N, 9.93. Found: C, 51.10; H, 2.81; N, 9.87.

2) To a solution of 6-fluoro-2-pyridinecarboxylic acid (15.0 g, 106.3mmol) in tetrahydrofuran (200 ml) was added1,1′-carbonylbis-1H-imidazole (19.0 g, 116.9 mmol), and the mixture washeated under reflux for 30 min. The reaction solution was cooled andmonoethyl malonate magnesium salt (16.8 g, 58.5 mmol) was added. Themixture was stirred at room temperature for 30 min. 1N Hydrochloric acid(200 ml) was added to the reaction solution and the mixture wasextracted with ethyl acetate (200 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) to give ethyl3-(6-fluoro-2-pyridyl)-3-oxopropionate (20.16 g, 90%) as a brown oil.

¹H-NMR (CDCl₃)δ: 1.20-1.40 (3H, m), 4.13 (2H×2/3, s), 4.14-4.34 (2H, m),6.30 (1H×1/3, s), 6.96-7.04 (1H×1/3, m), 7.12-7.24 (1H×2/3, m),7.78-8.04 (2H, m), 12.32 (1H×1/3, s). IR ν max^(KBr)cm⁻¹: 1744, 1709,1651, 1593, 1578, 1453. Anal. Calcd for C₁₀H₁₀FNO₃: C, 56.87; H, 4.77Found: C, 56.74; H, 4.73

3) To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (7.51 g, 35.6mmol) in carbon tetrachloride (100 ml) were added N-bromosuccinimide(7.60 g, 42.7 mmol) and 2,2′-azobis(isobutyronitrile) (290 mg, 1.78mmol), and the mixture was heated under reflux for 4 hrs. After cooling,the reaction solution was filtered, the filtrate was concentrated togive 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution ofethyl 3-(6-fluoropyridin-2-yl)-3-oxopropionate (7.51 g, 35.6 mmol) in1,2-dimethoxyethane (70 ml) was added sodium hydride (60% in oil, 1.42g, 35.6 mmol) under ice-cooling, and the mixture was stirred at roomtemperature for 30 min. To the reaction solution was dropwise added asolution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene preparedearlier in 1,2-dimethoxyethane (10 ml), and the reaction solution wasstirred at room temperature for 1 hr. The reaction solution was pouredinto water (100 ml), and the mixture was extracted with ethyl acetate(100 ml×2). The extract was washed with water and saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was purified by silica gel column chromatography(toluene:hexane=1:1) to give ethyl3-(6-fluoropyridin-2-yl)-3-oxo-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate(7.74 g, 52%) as a colorless oil.

¹H-NMR (CDCl₃)δ: 1.13 (3H, t, J=9.0 Hz), 3.20-3.44 (2H, m), 4.11 (2H, q,J=9.0 Hz), 4.98 (1H, t, J=7.4 Hz), 5.89 (1H, tt, J=53.0, 3.0 Hz),7.00-7.32 (5H, m), 7.90-8.04 (2H, m). IR ν max^(KBr)cm⁻¹: 1732, 1705,1593, 1453. Anal. Calcd for C₁₉H₁₆F₅NO₄: C, 54.68; H, 3.86; N, 3.36.Found: C, 54.55; H, 3.92; N, 3.51.

4) To a solution of zinc chloride (4.19 g, 30.7 mmol) in diethyl ether(100 ml) was added sodium borohydride (2.33 g, 61.4 mmol), and themixture was stirred at room temperature for 30 min. Insoluble materialwas filtered off, and a solution of ethyl3-(6-fluoropyridin-2-yl)-3-oxo-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate(6.41 g, 15.4 mmol) in diethyl ether (50 ml) was added to the filtrateat −78° C. The mixture was stirred for 30 min. 1N Hydrochloric acid wasadded to the reaction solution to quench the reaction. Then, water (100ml) was added and the mixture was extracted with ethyl acetate (200ml×2). The extract was washed with water and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1) to give ethyl3-(6-fluoropyridin-2-yl)-3-hydroxy-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate((2RS,3RS)form: (2RS,3SR) form=6:1, 5.70 g, 88%) as a colorless oil.

¹H-NMR (CDCl₃)δ: 0.96-1.00 (3H, m), 2.87 (1H, dd, J=5.0 Hz), 2.96-3.14(1H, m), 3.20-3.40 (1H, m), 3.76 (1H, d, J=5.6 Hz), 3.90-4.04 (2H, m),4.76 (1H×1/7, dd, J=9.6, 4.4 Hz), 5.00-5.08 (1H×6/7, m), 5.89 (1H, tt,J=53.0, 3.0 Hz), 6.83 (1H, dd, J=8.0, 2.6 Hz), 6.90-7.36 (5H, m),7.70-7.86 (1H, m). IR ν max^(KBr)cm⁻¹: 1728, 1607, 1578, 1454. Anal.Calcd for C₁₉H₁₈F₅NO₄: C, 54.42; H, 4.33; N, 3.34. Found: C, 54.34; H,4.37; N, 3.29.

5) To a solution ofethyl(2RS,3RS)-3-(6-fluoropyridin-2-yl)-3-hydroxy-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate(5.5 g, 13.1 mmol, (2RS,3RS) form: (2RS,3SR) form=6:1) in methanol (25ml) was added 2N aqueous sodium hydroxide solution (13.1 ml, 26.2 mmol),and the mixture was stirred at room temperature for 2 hrs. The reactionsolution was acidified with 1N hydrochloric acid and extracted withethyl acetate (200 ml×2). The extract was washed with water andsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. Recrystallization of the residue from ethylacetate-hexane gave(2RS,3RS)-3-(6-fluoropyridin-2-yl)-3-hydroxy-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionicacid (3.82 g, 74%).

¹H-NMR (CDCl₃)δ: 2.85 (1H, dd, J=14.0, 5.2 Hz), 3.08 (1H, dd, J=14.0,9.0 Hz), 3.26-3.38 (1H, m), 5.12 (1H, d, J=4.4 Hz), 5.88 (1H, tt,J=53.0, 3.0 Hz), 6.81 (1H, dd, J=8.2, 2.6 Hz), 6.90-7.04 (3H, m), 7.18(1H, d, J=7.6 Hz), 7.27 (1H, dd, J=7.2, 2.2 Hz), 7.70-7.82 (1H, m). IR νmax^(KBr)cm⁻¹: 1713, 1609, 1580, 1489, 1456. mp 103-104° C. Anal. Calcdfor C₁₇H₁₄F₅NO₄: C, 52.18; H, 3.61; N, 3.58. Found: C, 52.16; H, 3.57;N, 3.57.

6) To a solution of(2RS,3RS)-3-(6-fluoropyridin-2-yl)-3-hydroxy-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionicacid (3.6 g, 9.20 mmol) in tetrahydrofuran (90 ml) were addeddiphenylphosphoryl azide (2.18 ml, 10.1 mmol) and triethylamine (1.93ml, 13.8 mmol), and the mixture was heated under reflux for 2 hrs. Thereaction solution was allowed to cool and water (200 ml) was added. Themixture was extracted with ethyl acetate (100 ml×2). The extract waswashed successively with 1N hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=1:1).Recrystallization from ethyl acetate-hexane gave(4RS,5RS)-5-(6-fluoropyridin-2-yl)-4-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidin-2-one(2.34 g, 65%).

¹H-NMR (CDCl₃)δ: 2.14 (1H, dd, J=13.6, 9.0 Hz), 2.58 (1H, dd, J=13.6,3.2 Hz), 4.36-4.50 (1H, m), 5.13 (1H, s), 5.78 (1H, d, J=8.0 Hz), 5.91(1H, tt, J=53.0, 3.0 Hz), 6.90-7.20 (4H, m), 7.26-7.42 (1H, m), 7.52(1H, d, J=5.2 Hz), 7.86-8.00 (1H, m). IR ν max^(KBr)cm⁻¹: 1767, 1607,1584, 1489, 1458, 1447. mp 118-119° C. Anal. Calcd for C₁₇H₁₃F₅N₂O₃: C,52.59; H, 3.37; N, 7.21. Found: C, 52.60; H, 3.31; N, 7.35.

7) To a solution of(4RS,5RS)-5-(6-fluoropyridin-2-yl)-4-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidin-2-one(2.2 g, 5.67 mmol) in acetonitrile (20 ml) were added di-t-butyldicarbonate (1.48 g, 6.80 mmol) and dimethylaminopyridine (70 mg, 0.57mmol), and the mixture was stirred at room temperature for 2 hrs. To thereaction solution was added water (50 ml), and the mixture was extractedwith ethyl acetate (50 ml×2). The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) and recrystallized from ethylacetate-hexane to give1,1-dimethylethyl(4RS,5RS)-5-(6-fluoropyridin-2-yl)-2-oxo-4-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidine-3-carboxylate(2.59 g, 94%).

¹H-NMR (CDCl₃)δ: 1.45 (9H, s), 2.65 (1H, dd, J=14.2, 7.4 Hz), 2.84 (1H,dd, J=14.2, 5.8 Hz), 4.97-5.08 (1H, m), 5.61 (1H, d, J=6.4 Hz), 5.88(1H, tt, J=53.0, 3.0 Hz), 6.53 (1H, s), 6.75 (1H, d, J=7.6 Hz), 6.88(1H, dd, J=8.0, 2.6 Hz), 7.02 (1H, d, J=9.6 Hz), 7.10-7.22 (1H, m), 7.43(1H, dd, J=7.4, 2.6 Hz), 7.80-7.94 (1H, m). IR ν max^(KBr)cm⁻¹: 1823,1728, 1607, 1584, 1460, 1447. mp 96-97° C. Anal. Calcd for C₂₂H₂₁F₅N₂O₅:C, 54.10; H, 4.33; N, 5.74. Found: C, 54.14; H, 4.25; N, 5.78.

8) To a solution of1,1-dimethylethyl(4RS,5RS)-5-(6-fluoropyridin-2-yl)-2-oxo-4-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidine-3-carboxylate(2.40 g, 4.91 mmol) in methanol (12 ml) was added a solution (11.8 ml,5.90 mmol) of 0.5N sodium hydroxide in methanol, and the mixture wasstirred at room temperature for 10 min. To the reaction solution wasadded water (50 ml) and the mixture was extracted with ethyl acetate (50ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to give the title compound(1.92 g, 84%).

¹H-NMR (CDCl₃)δ: 1.37 (9H, s), 2.65 (1H, dd, J=13.6, 5.0 Hz), 2.85 (1H,dd, J=13.6, 9.0 Hz), 4.08-4.30 (1H, m), 4.45 (1H, d, J=6.0 Hz),4.88-5.02 (2H, m), 5.89 (1H, tt, J=53.0, 3.0 Hz), 6.85 (1H, dd, J=8.0,2.2 Hz), 6.90-7.10 (3H, m), 7.10-7.32 (2H, m), 7.70-7.86 (1H, m). IR νmax^(KBr)cm⁻¹: 1682, 1607, 1576, 1532, 1487, 1454. mp 140-141° C. Anal.Calcd for C₂₁H₂₃F₅N₂O₄: C, 54.55; H, 5.01; N, 6.06. Found: C, 54.27; H,4.71; N, 6.12.

Example 222N-((1RS,2RS)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1) To a solution of1,1-dimethylethyl(1RS,2RS)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethylcarbamate(1.6 g, 3.46 mmol) was added trifluoroacetic acid (20 ml), and themixture was stirred at room temperature for 10 min. The reactionsolution was concentrated under reduced pressure, and 1N aqueous sodiumhydroxide solution (10 ml) was added. The mixture was extracted withethyl acetate (20 ml×2). The extract was washed with saturated brine,dried over anhydrous magnesium sulfate and evaporated under reducedpressure to give(1RS,2RS)-2-amino-1-(6-fluoropyridin-2-yl)-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol(1.3 g, 100%).

¹H-NMR (CDCl₃)δ: 2.47 (1H, dd, J=13.8, 10.0 Hz), 2.73 (1H, dd, J=13.8,3.4 Hz), 3.40-3.54 (1H, m), 4.70 (1H, d, J=4.4 Hz), 5.90 (1H, tt,J=53.0, 3.0 Hz), 6.86 (1H, dd, J=8.0, 2.6 Hz), 6.96-7.18 (3H, m),7.20-7.40 (2H, m), 7.78-7.92 (1H, m). IR ν max^(KBr)cm⁻¹: 1755, 1607,1578, 1489, 1454. Anal. Calcd for C₁₆H₁₅F₅N₂O₂: C, 53.04; H, 4.17; N,7.73. Found: C, 53.19; H, 4.40; N, 7.51.

2) To a solution of(1RS,2RS)-2-amino-1-(6-fluoropyridin-2-yl)-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol(300 mg, 0.83 mmol) in acetonitrile (20 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (156 mg, 0.83mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (238mg, 1.24 mmol) and 1-hydroxy-1H-benzotriazole (127 mg, 0.83 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with 1Nhydrochloric acid, 1N aqueous sodium hydroxide solution and saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. Recrystallization of the residue from ethylacetate-hexane gave the title compound (293 mg, 66%).

¹H-NMR (CDCl₃)δ: 1.92-2.10 (2H, m), 2.12-2.26 (2H, m), 2.60-2.70 (2H,m), 2.81 (1H, dd, J=14.6, 5.2 Hz), 3.03 (1H, dd, J=14.6, 9.8 Hz),4.66-4.82 (1H, m), 4.84 (1H, d, J=5.8 Hz), 5.02-5.10 (1H, m), 5.89 (1H,tt, J=53.0, 3.0 Hz), 5.90-6.02 (1H, m), 6.18-6.32 (2H, m), 6.86 (1H, dd,J=8.0, 2.6 Hz), 7.00-7.30 (7H, m), 7.42 (1H, dd, J=7.4, 2.2 Hz),7.76-7.90 (1H, m). IR ν max^(KBr)cm⁻¹: 1642, 1607, 1578, 1516, 1454. mp151-152° C. Anal. Calcd for C₂₈H₂₅F₅N₂O₃.0.2H₂O: C, 62.73; H, 4.78; N,5.23. Found: C, 62.75; H, 4.75; N, 5.31.

Example 2231,1-dimethylethyl(1RS,2SR)-2-(6-fluoropyridin-3-yl)-2-hydroxy-1-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethylcarbamate

1) To a solution of 2-amino-5-methylpyridine (75 g, 693 mmol) in 42%tetrafluoroboric acid (291 ml) was added a solution of sodium nitrite(47.8 g, 693 mmol) in water (100 ml) while cooling with dry ice-acetoneso that the inside temperature would not exceed 10° C. After thereaction solution was stirred at 45° C. for 30 min., 8N aqueous sodiumhydroxide solution (100 ml) was gradually added, and the mixture wasextracted with diethyl ether (300 ml×2). The extract was concentratedunder reduced pressure and the residue was distilled away to give2-fluoro-5-methylpyridine (30.4 g). A solution of potassium permanganate(100 g, 632 mmol) in water (1.2 L) was heated to 80° C. and2-fluoro-5-methylpyridine (30.4 g, 274 mmol) was added. The mixture washeated under reflux for 4.5 hrs. Insoluble material was filtered offwith celite from the reaction solution, and the filtrate wasconcentrated to 200 ml. Then, 6N hydrochloric acid was added until thepH became about 3. The precipitated crystals were collected byfiltration to give 6-fluoro-3-pyridinecarboxylic acid (10.58 g, 11%).

mp 151-152° C. IR ν max^(KBr)cm⁻¹: 3100, 1730, 1620. Anal. Calcd forC₆H₄FNO₂: C, 51.07; H, 2.86; N, 9.93. Found: C, 50.78; H, 2.72; N, 9.87.¹H-NMR (CDCl₃)δ: 7.07 (1H, dd, J=8.8, 2.8 Hz), 8.40-8.52 (1H, m),8.90-9.04 (1H, m).

2) To a solution of 6-fluoro-3-pyridinecarboxylic acid (9.5 g, 67.3mmol) in tetrahydrofuran (150 ml) was added1,1′-carbonylbis-1H-imidazole (12.0 g, 74.1 mmol), and the mixture wasstirred at 80° C. for 10 min. The reaction solution was cooled to roomtemperature and monoethyl malonate magnesium salt (10.6 g, 37.0 mmol)was added. The mixture was stirred at room temperature for 2 hrs. To thereaction solution were added ethyl acetate (100 ml) and water (100 ml).Then, conc. hydrochloric acid was added until the aqueous layer showedacidic pH. The reaction solution was extracted with ethyl acetate (200ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=4:1)to give ethyl 3-(6-fluoropyridin-3-yl)-3-oxopropionate (9.74 g, 68%) asa brown oil.

IR ν max^(KBr)cm⁻¹: 1738, 1694, 1634, 1593, 1485. Anal. Calcd forC₁₀H₁₀NO₃F: C, 56.87; H, 4.77; N, 6.63. Found: C, 56.79; H, 4.78; N,6.84. ¹H-NMR (CDCl₃)δ: 1.27 (3H×5/7, t, J=7.0 Hz), 1.35 (3H×2/7, t,J=7.4 Hz), 3.99 (2H×5/7, s), 4.16-4.36 (2H, m), 5.65 (1H×2/7, s),6.96-7.10 (1H, m), 8.16 (1H×2/7, td, J=9.0, 3.8 Hz), 8.39 (1H×5/7, td,J=9.0, 3.8 Hz), 8.64 (1H×2/7, d, J=3.8 Hz), 8.81 (1H×5/7, d, J=3.8 Hz).

3) To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (15 g, 72.1mmol) in chloroform (200 ml) were added N-bromosuccinimide (14.11 g,79.3 mmol) and 2,2′-azobis(isobutyronitrile) (590 mg, 3.60 mmol), andthe mixture was heated under reflux for 30 min. The reaction solutionwas cooled and water (100 ml) was added. The mixture was extracted withchloroform. The extract was washed successively with water (100 ml) andsaturated brine (100 ml), dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=10:1) to give3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene (19.4 g, purity 56%, 53%).This compound was used for the next reaction without furtherpurification.

4) To a solution of ethyl 3-(6-fluoropyridin-3-yl)-3-oxopropionate (3.83g, 18.1 mmol) in 1,2-dimethoxyethane (30 ml) was added sodium hydride(60% in oil, 725 mg, 18.1 mmol) under ice-cooling, and the mixture wasstirred at room temperature for 30 min. To the reaction solution wasdropwise added 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene (9.30 g,purity 56%, 18.1 mmol) in 1,2-dimethoxyethane (10 ml), and the mixturewas stirred at room temperature for 2 hrs. The reaction solution waspoured into water (100 ml), and the mixture was extracted with ethylacetate (100 ml×2). The extract was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (toluene-toluene:ethyl acetate=5:1) to give ethyl3-(6-fluoropyridin-3-yl)-3-oxo-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate(6.67 g, 88%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1738, 1694, 1590, 1487. Anal. Calcd for C₁₉H₁₆F₅NO₄:C, 54.68; H, 3.86; N, 3.36. Found: C, 54.56; H, 4.13; N, 3.51. ¹H-NMR(CDCl₃)δ: 1.14 (3H, t, J=7.0 Hz), 3.36 (2H, d, J=7.4 Hz), 4.13 (2H, q,J=7.0 Hz), 4.54 (1H, d, J=7.4 Hz), 5.89 (1H, tt, J=53.0, 2.8 Hz),6.98-7.20 (4H, m), 7.20-7.36 (1H, m), 8.35 (1H, td, J=8.4, 2.4 Hz), 8.82(1H, d, J=2.4 Hz).

5) To a solution of zinc chloride (4.25 g, 31.2 mmol) in diethyl ether(100 ml) was added sodium borohydride (2.36 g, 62.3 mmol), and themixture was stirred at room temperature for 30 min. Insoluble materialwas filtered off and a solution of ethyl3-(6-fluoropyridin-3-yl)-3-oxo-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate(6.50 g, 15.6 mmol) in diethyl ether (50 ml) was added to the filtrate.The mixture was stirred at room temperature for 30 min. and 1Nhydrochloric acid was added to the reaction solution under ice-coolingto quench the reaction. Then, water (100 ml) was added and the mixturewas extracted with ethyl acetate (200 ml×2). The extract was washed withwater and saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1-1:1) to giveethyl(2RS,3RS)-3-(6-fluoropyridin-3-yl)-3-hydroxy-2-1((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate((1RS,2SR)form: (1RS,2RS) form=10:1,5.15 g, 79%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1728, 1601, 1487. Anal. Calcd forC₁₉H₁₈F₅NO₄.0.1H₂O: C, 54.19; H, 4.35; N, 3.33. Found: C, 54.10; H,4.20; N, 3.39. ¹H-NMR (CDCl₃)δ: 0.95 (3H×10/11, t, J=7.0 Hz), 1.02(3H×1/11, t, J=7.4 Hz), 2.80-3.16 (3H, m), 3.23 (1H, d, J=3.0 Hz),3.84-4.00 (2H, m), 4.80-4.90 (1H×1/11, m), 5.09 (1H×10/11, s), 5.89 (1H,tt, J=53.0, 3.0 Hz), 6.90-7.12 (4H, m), 7.20-7.30 (1H, m), 7.86 (1H, td,J=8.2, 2.6 Hz), 8.16-8.24 (1H, m).

6) To a solution ofethyl(2RS,3RS)-3-(6-fluoropyridin-3-yl)-3-hydroxy-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate(5.0 g, 11.9 mmol, (2RS,3SR) form: (2RS,3RS) form=10:1) in methanol (20ml) was added 2N aqueous sodium hydroxide solution (11.9 ml, 23.8 mmol),and the mixture was stirred overnight at room temperature. The reactionsolution was acidified with 1N hydrochloric acid and extracted withethyl acetate (200 ml×2). The extract was washed with water andsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate) to give(2RS,3RS)-3-(6-fluoropyridin-3-yl)-3-hydroxy-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionicacid (3.75 g, (2RS,3SR) form: (2RS,3RS) form=10:1, 80%) as an amorphouscompound.

IR ν max^(KBr)cm⁻¹: 1715, 1607, 1593, 1487. Anal. Calcd for C₁₇H₁₄F₅NO₄:C, 52.18; H, 3.61; N, 3.58. Found: C, 52.13; H, 3.43; N, 3.57. ¹H-NMR(CDCl₃)δ: 2.80-3.12 (3H, m), 4.85 (1H×1/11, d, J=5.2 Hz), 5.10(1H×10/11, s), 6.88-7.12 (4H, m), 7.22 (1H, t, J=7.6 Hz), 7.87 (1H, td,J=7.6, 2.2 Hz), 8.14 (1H, s).

7) To a solution of(2RS,3RS)-3-(6-fluoropyridin-3-yl)-3-hydroxy-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionicacid (3.6 g, 9.20 mmol, (2RS,3SR) form: (2RS,3RS) form=10:1) intetrahydrofuran (90 ml) were added diphenylphosphoryl azide (2.18 ml,10.1 mmol) and triethylamine (1.93 ml, 13.8 mmol), and the mixture washeated under reflux for 30 min. The reaction solution was allowed tocool and water (200 ml) was added. The mixture was extracted with ethylacetate (100 ml×2). The extract was washed successively with 1Nhydrochloric acid, saturated aqueous sodium hydrogen carbonate andsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:1) to give(4RS,5SR)-5-(6-fluoropyridin-3-yl)-4-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidin-2-one(3.31 g, (4RS,5SR) form: (4RS,5RS) form=10:1, 93%) as an amorphouscompound.

IR ν max^(KBr)cm⁻¹: 1767, 1603, 1489. Anal. Calcd for C₁₇H₁₃F₅N₂O₃: C,52.59; H, 3.37; N, 7.21. Found: C, 52.46; H, 3.55; N, 7.03. ¹H-NMR(CDCl₃)δ: 2.34 (1H, d, J=4.0 Hz), 2.38 (1H, s), 4.04-4.20 (1H×1/11, m),4.28-4.42 (1H×10/11, m), 5.25 (1H×1/11, s), 5.29 (1H×10/11, s), 5.84(1H, d, J=8.0 Hz), 5.91 (1H, tt, J=53.0, 3.0 Hz), 6.86-7.18 (4H, m),7.22-7.40 (1H, m), 7.60-7.78 (1H×1/11, m), 7.85 (1H×10/11, td, J=8.2,2.6 Hz), 8.02 (1H×1/11, s), 8.22 (1H×10/11, s).

8) To a solution of(4RS,5SR)-5-(6-fluoropyridin-3-yl)-4-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidin-2-one(3.10 g, 7.98 mmol) in acetonitrile (30 ml) were added di-t-butyldicarbonate (2.09 g, 9.58 mmol) and dimethylaminopyridine (97 mg, 0.80mmol), and the mixture was stirred at room temperature for 2 hrs. Water(50 ml) was added to the reaction solution, and the mixture wasextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) and recrystallized from ethylacetate-hexane to give1,1-dimethylethyl(4RS,5SR)-5-(6-fluoropyridin-3-yl)-2-oxo-4-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidine-3-carboxylate(2.55 g, 65%).

mp 138-139° C. IR ν max^(KBr)cm⁻¹: 1821, 1725, 1603. Anal. Calcd forC₂₂H₂₁F₅N₂O₅: C, 54.10; H, 4.33; N, 5.74. Found: C, 54.14; H, 4.41; N,5.77. ¹H-NMR (CDCl₃)δ: 1.54 (9H, s), 2.06 (1H, dd, J=14.2, 9.6 Hz), 3.04(1H, dd, J=14.2, 4.0 Hz), 4.82-4.96 (1H, m), 5.72 (1H, d, J=6.8 Hz),5.89 (1H, tt, J=53.0, 3.0 Hz), 6.52-6.62 (2H, m), 6.81 (1H, dd, J=8.4,2.8 Hz), 6.94-7.04 (1H, m), 7.04-7.20 (1H, m), 7.53 (1H, td, J=8.0, 2.6Hz), 8.05 (1H, d, J=2.0 Hz).

9) To absolution of1,1-dimethylethyl(4RS,5SR)-5-(6-fluoropyridin-3-yl)-2-oxo-4-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidine-3-carboxylate(2.40 g, 4.91 mmol) in methanol (12 ml) was added a solution of 0.5Nsodium hydroxide in methanol (11.8 ml, 5.90 mmol), and the mixture wasstirred at room temperature for 10 min. To the reaction solution wasadded water (50 ml) and the mixture was extracted with ethyl acetate (50ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to give the title compound(1.98 g, 87%).

mp 128-129° C. IR ν max^(KBr)cm⁻¹: 1694, 1601, 1487. Anal. Calcd forC₂₁H₂₃F₅N₂O₄: C, 54.55; H, 5.01; N, 6.06. Found: C, 54.49; H, 5.01; N,6.23. ¹H-NMR (CDCl₃)δ: 1.34 (9H, s), 2.62-2.90 (2H, m), 3.92 (1H, brs),3.98-4.16 (1H, m), 4.62 (1H, d, J=7.4 Hz), 4.94 (1H, s), 5.90 (1H, tt,J=53.0, 3.0 Hz), 6.90-7.12 (4H, m), 7.22-7.32 (1H, m), 7.80-7.92 (1H,m), 8.21 (1H, s).

Example 224N-((1RS,2SR)-2-(6-fluoropyridin-3-yl)-2-hydroxy-1-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethyl)-4-fluoro-1-naphthalenecarboxamide

1) To a solution of1,1-dimethylethyl(1RS,2SR)-2-(6-fluoropyridin-3-yl)-2-hydroxy-1-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethylcarbamate(1.0 g, 2.16 mmol) was added trifluoroacetic acid (10 ml), and themixture was stirred at room temperature for 10 min. The reactionsolution was concentrated under reduced pressure and 1N aqueous sodiumhydroxide solution (10 ml) was added. The mixture was extracted withethyl acetate (20 ml×2). The extract was washed with saturated brine,dried over anhydrous magnesium sulfate and evaporated under reducedpressure. The residue was recrystallized from ethyl acetate-hexane togive(1RS,2SR)-2-amino-1-(6-fluoropyridin-3-yl)-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol(750 mg, 96%).

mp 103-104° C. IR ν max^(KBr)cm⁻¹: 1597, 1485, 1449, 1399. Anal. Calcdfor C₁₆H₁₅F₅N₂O₂: C, 53.04; H, 4.17; N, 7.73. Found: C, 52.97; H, 4.17;N, 7.84. ¹H-NMR (CDCl₃)δ: 2.38 (1H, dd, J=13.4, 10.4 Hz), 2.74 (1H, dd,J=13.4, 3.0 Hz), 3.28-3.40 (1H, m), 4.76 (1H, d, J=4.4 Hz), 5.90 (1H,tt, J=53.0, 3.0 Hz), 6.90-7.12 (4H, m), 7.22-7.40 (1H, m),7.88 (1H, td,J=8.2, 2.6 Hz), 8.23 (1H, s).

2) To a solution of(1RS,2SR)-2-amino-1-(6-fluoropyridin-3-yl)-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol(191 mg, 0.53 mmol) in acetonitrile (20 ml) were added4-fluoronaphthalenecarboxylic acid (100 mg, 0.53 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg,0.79 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol), and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure.Recrystallization of the residue from ethyl acetate-hexane gave thetitle compound (130 mg, 48%).

mp 148-149° C. IR ν max^(KBr)cm⁻¹: 1640, 1626, 1601, 1514, 1485. Anal.Calcd for C₂₇H₂₀F₆N₂O₃: C, 60.68; H, 3.77; N, 5.24. Found: C, 60.87; H,3.87; N, 5.11. ¹H-NMR (CDCl₃)δ: 2.84 (1H, dd, J=14.2, 10.6 Hz), 3.09(1H, dd, J=14.2, 4.0 Hz), 4.02 (1H, brs), 4.64-4.82 (1H, m), 5.15 (1H,d, J=4.0 Hz), 5.89 (1H, tt, J=53.0, 3.0 Hz), 5.97 (1H, d, J=8.4 Hz),6.90-7.70 (9H, m), 7.78-7.90 (1H, m), 7.97 (1H, td, J=8.0, 2.2 Hz), 8.09(1H, d, J=7.2 Hz), 8.26 (1H, s).

Example 225N-((1RS,2SR)-2-(6-fluoropyridin-3-yl)-2-hydroxy-1-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-1-(6-fluoropyridin-3-yl)-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol(193 mg, 0.53 mmol) in acetonitrile (20 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (100 mg, 0.53mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153mg, 0.80 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with 1Nhydrochloric acid, 1N aqueous sodium hydroxide solution and saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. Recrystallization of the residue from ethylacetate-hexane gave the title compound (232 mg, 82%).

mp 140-142° C. IR ν max^(KBr)cm⁻¹: 1636, 1597, 1487. ¹H-NMR (CDCl₃)δ:1.90-2.10 (2H, m), 2.10-2.28 (2H, m), 2.58-2.72 (2H, m), 2.79 (1H, dd,J=14.4, 10.8 Hz), 3.03 (1H, dd, J=14.4, 4.0 Hz), 4.26 (1H, brs),4.58-4.74 (1H, m), 5.07 (1H, d, J=3.6 Hz), 5.80 (1H, d, J=7.6 Hz), 5.89(1H, tt, J=53.0, 3.0 Hz), 5.90-6.00 (1H, m), 6.10-6.24 (1H, m),6.90-7.22 (7H, m), 7.22-7.40 (1H, m), 7.94 (1H, td, J=8.0, 2.2 Hz), 8.23(1H, s).

Example 226 Optical Resolution ofN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]naphthalene-1-carboxamide

The racemate was optically resolved by high performance liquidchromatography using an optically active column (CHIRALCELL OD, 50mmID×500 mmL) (mobile layer: hexane/ethanol=9/1), and each opticalisomer was obtained by recrystallization from ethanol.

(1R,2S) form mp 239-240° C.; [α]_(D) ²⁰ +37.3° (c=0.507, MeOH); ¹H-NMR(CDCl₃-CD₃OD, 200 MHz) δ 2.85 (1H, dd, J=10.8 Hz, 14.0 Hz), 3.08 (1H,dd, J=3.6 Hz, 13.8 Hz), 4.72-4.87 (1H, m), 5.02 (1H, d, J=4.6 Hz), 6.79(1H, br d, J=8.8 Hz), 7.10 (2H, t, J=8.6 Hz), 7.21 (1H, d, J=7.0 Hz),7.30-7.57 (10H, m), 7.77-7.88 (2H, m); IR (KBr) 3268, 1638, 1534, 1514,1325, 1229, 1163, 1123, 1069, 831 cm⁻¹; Anal. Calcd for C₂₇H₂₁F₄NO₂: C,69.37; H, 4.53; N, 3.00. Found: C, 69.30; H, 4.27; N, 2.76.

(1S,2R) form mp 238-239° C.; [α] _(D) ²⁰ −37.9° (c=0.508, MeOH); ¹H-NMR(CDCl₃-CD₃OD, 200 MHz) δ 2.85 (1H, dd, J=11.4 Hz, 14.2 Hz), 3.09 (1H,dd, J=3.9 Hz, 13.7 Hz), 4.72-4.86 (1H, m), 5.01 (1H, d, J=4.8 Hz), 6.90(1H, br d, J=9.6 Hz), 7.11 (2H, t, J=8.8 Hz), 7.20 (1H, dd, J=1.2 Hz,7.0 Hz), 7.29-7.57 (10H, m), 7.79-7.88 (2H, m); IR (KBr) 3279, 1638,1534, 1514, 1325, 1229, 1163, 1123, 1069, 833 cm⁻¹; Anal. Calcd forC₂₇H₂₁F₄NO₂: C, 69.37; H, 4.53; N, 3.00. Found: C, 69.28; H, 4.50; N,2.98.

Example 227 Optical Resolution of4-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]naphthalene-1-carboxamide

The racemate was optically resolved by high performance liquidchromatography using an optically active column (CHIRALCELL OD, 50mmID×500 mmL) (mobile layer:hexane/ethanol=95/5), and each opticalisomer was obtained by recrystallization from ethanol-diisopropyl ether.

(1R,2S) form mp 251-252° C.; [α] _(D) ²⁰ +33.4° (c=0.499, MeOH); ¹H-NMR(CDCl₃-DMSO-d₆, 200 MHz) δ 2.92 (1H, dd, J=11.0 Hz, 13.8 Hz), 3.19 (1H,dd, J=3.3 Hz, 14.3 Hz), 4.62-4.76 (1H, m), 4.89 (1H, t, J=5.2 Hz), 5.49(1H, d, J=4.4 Hz), 7.01-7.18 (4H, m), 7.32-7.42 (4H, m), 7.48-7.60 (5H,m), 7.91 (1H, d, J=9.6 Hz), 8.03 (1H, d, J=8.6 Hz); IR (KBr) 3275, 1642,1626, 1539, 1514, 1327, 1229, 1167, 1125, 1069, 835 cm⁻¹; Anal. Calcdfor C₂₇H₂₀F₅NO₂: C, 66.80; H, 4.15; N, 2.89. Found: C, 66.55; H, 4.16;N, 2.76.

(1S,2R) form mp 252-253° C.; [α] _(D) ²⁰ −33.9° (c=0.504, MeOH); ¹H-NMR(CDCl₃-DMSO-d₆, 200 MHz) δ 2.93 (1H, dd, J=11.0 Hz, 14.0 Hz), 3.15 (1H,dd, J=3.2 Hz, 14.0 Hz), 4.66-4.79 (1H, m), 4.93 (1H, t, J=4.8 Hz), 5.42(1H, d, J=3.6 Hz), 7.01-7.21 (4H, m), 7.34-7.60 (9H, m), 7.78 (1H, d,J=9.6 Hz), 8.04 (1H, d, J=8.2 Hz); IR (KBr) 3275, 1642, 1626, 1539,1514, 1327, 1227, 1167, 1125, 1069, 835 cm⁻¹; Anal. Calcd forC₂₇H₂₀F₅NO₂: C, 66.80; H, 4.15; N, 2.89. Found: C, 66.69; H, 4.09; N,2.82.

Example 228 Optical Resolution of4-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]naphthalene-1-carboxamide

The racemate was optically resolved by high performance liquidchromatography using an optically active column (CHIRALCELL OD, 50mmID×500 mmL) (mobile layer: hexane/ethanol=95/5), and each opticalisomer was obtained by recrystallization from ethyl acetate-diisopropylether-hexane.

(1R,2S) form mp 213-214° C.; [α] _(D) ²⁰ +20.6° (c=0.506, MeOH); ¹H-NMR(CDCl₃-DMSO-d₆, 200 MHz) δ 2.82-3.03 (2H, m), 4.70-4.84 (2H, m), 5.07(1H, t, J=3.3 Hz), 5.90 (1H, tt, J=2.8 Hz, 53.0 Hz), 6.92 (1H, d, J=9.4Hz), 6.98-7.33 (8H, m), 7.42-7.57 (4H, m), 7.79 (1H, d, J=8.4 Hz), 8.07(1H, d, J=7.4 Hz); IR (KBr) 3270, 1642, 1624, 1601, 1537, 1512, 1235,1198, 1127, 835, 760 cm⁻¹; Anal. Calcd for C₂₈H₂₁F₆NO₃: C, 63.04; H,3.97; N, 2.63. Found: C, 62.87; H, 3.84; N, 2.64.

(1S,2R) form mp 213-214° C.; [α] _(D) ²⁰ −20.6° (c=0.520, MeOH); ¹H-NMR(CDCl₃-DMSO-d₆, 200 MHz) δ 2.82-3.03 (2H, m), 4.70-4.85 (2H, m), 5.07(1H, t, J=3.7 Hz), 5.90 (1H, tt, J=2.9 Hz, 53.0 Hz), 6.92 (1H, d, J=8.8Hz), 6.98-7.33 (8H, m), 7.40-7.58 (4H, m), 7.80 (1H, d, J=8.0 Hz), 8.07(1H, d, J=7.8 Hz); IR (KBr) 3272, 1642, 1624, 1601, 1537, 1512, 1235,1198, 1127, 835, 760 cm⁻¹; Anal. Calcd for C₂₈H₂₁F₆NO₃: C, 63.04; H,3.97; N, 2.63. Found: C, 62.97; H, 3.87; N, 2.57.

Example 229 Optical Resolution ofN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[α] cycloheptene-1-carboxamide

The racemate was optically resolved by high performance liquidchromatography using an optically active column (CHIRALCELL OD, 50mmID×500 mmL) (mobile layer: hexane/ethanol=95/5), and each opticalisomer was obtained by recrystallization from ethyl acetate-diisopropylether-hexane.

(1R,2S) form mp 199-200° C.; [α] _(D) ²⁰ +20.3° (c=0.536, MeOH); ¹H-NMR(CDCl₃, 200 MHz) δ 1.93-2.06 (2H, m), 2.15-2.24 (2H, m), 2.67 (2H, t,J=5.7 Hz), 2.79 (1H, dd, J=10.8 Hz, 14.4 Hz), 3.00 (1H, dd, J=3.7 Hz,14.5 Hz), 3.59 (1H, d, J=3.6 Hz), 4.60-4.74 (1H, m), 5.04 (1H, t, J=3.7Hz), 5.72 (1H, d, J=8.8 Hz), 5.89 (1H, tt, J=2.8 Hz, 53.0 Hz), 5.91 (1H,td, J=5.3 Hz, 11.6 Hz), 6.21 (1H, d, J=11.6 Hz), 6.95-7.17 (8H, m), 7.31(1H, t, J=8.0 Hz), 7.44 (2H, dd, J=5.3 Hz, 8.7 Hz); IR (KBr) 3264, 1640,1512, 1227, 1198, 1128 cm⁻¹; Anal. Calcd for C₂₉H₂₆F₅NO₃: C, 65.53; H,4.93; N, 2.64. Found: C, 65.52; H, 4.85; N, 2.63.

(1S,2R) form mp 200-201° C.; [α] _(D) ²⁰ −20.8° (c=0.544, MeOH); ¹H-NMR(CDCl₃, 200 MHz) δ 1.93-2.06 (2H, m), 2.15-2.24 (2H, m), 2.67 (2H, t,J=5.8 Hz), 2.79 (1H, dd, J=10.6 Hz, 14.6 Hz), 3.00 (1H, dd, J=4.3 Hz,14.7 Hz), 3.59 (1H, d, J=3.8 Hz), 4.60-4.74 (1H, m), 5.04 (1H, t, J=3.7Hz), 5.72 (1H, d, J=8.8 Hz), 5.89 (1H, tt, J=3.0 Hz, 53.1 Hz), 5.91 (1H,td, J=5.3 Hz, 12.0 Hz), 6.21 (1H, d, J=12.0 Hz), 6.95-7.17 (8H, m), 7.31(1H, t, J=7.6 Hz), 7.44 (2H, dd, J=5.4 Hz, 8.6 Hz); IR (KBr) 3264, 1637,1512, 1227, 1198, 1130 cm⁻¹; Anal. Calcd for C₂₉H₂₆F₅NO₃: C, 65.53; H,4.93; N, 2.64. Found: C, 65.56; H, 4.87; N, 2.64.

Example 230N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((5-methyl-3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethyl)-4-fluoro-1-naphthalenecarboxamide

1) To a solution of 3,5-dimethyl1-(1,1,2,2-tetrafluoropropyloxy)benzene(8.22 g, 32.8 mmol) in carbon tetrachloride (100 ml) were addedN-bromosuccinimide (6.42 g, 36.1 mmol) and 2,2′-azobis(isobutyronitrile)(270 mg, 1.64 mmol), and the mixture was heated under reflux overnight.Insoluble material was filtered off with celite, and the filtrate wasconcentrated to give a bromo form. To a solution of ethyl3-(4-fluorophenyl)-3-oxopropionate (6.20 g, 29.5 mmol) in1,2-dimethoxyethane (60 ml) was added sodium hydride (60% in oil, 1.18g, 29.5 mmol) under ice-cooling, and the mixture was stirred at roomtemperature for 30 min. To the reaction solution was dropwise added asolution of the bromo form synthesized earlier in 1,2-dimethoxyethane(20 ml), and the mixture was stirred at room temperature for 1 hr. Thereaction solution was poured into water (200 ml), and the mixture wasextracted with ethyl acetate (200 ml×2). The extract was washed withwater and saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (toluene:hexane=1:1-ethyl acetate).Recrystallization from ethyl acetate-hexane gave ethyl3-(4-fluorophenyl)-2-((3-methyl-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-3-oxopropionate(6.68 g, 53%).

mp 56-57° C. IR ν max^(KBr)cm⁻¹: 1738, 1688, 1599, 1508. Anal. Calcd forC₂₁H₁₉F₅O₄: C, 58.12; H, 4.50 Found: C, 57.94; H, 4.27. ¹H-NMR (CDCl₃)δ:1.13 (3H, t, J=7.0 Hz), 2.30 (3H, s), 3.28 (2H, d, J=7.4 Hz), 4.12 (2H,q, J=7.0 Hz), 4.54 (1H, t, J=7.4 Hz), 5.87 (1H, tt, J=53.0, 3.0 Hz),6.87 (2H, s), 6.94 (1H, s), 7.12 (2H, t, J=8.4 Hz), 7.92-8.06 (2H, m).

2) To a solution of zinc chloride (4.12 g, 30.2 mmol) in diethyl ether(100 ml) was added sodium borohydride (2.29 g, 60.4 mmol), and themixture was stirred at room temperature for 30 min. Insoluble materialwas filtered off, and a solution of ethyl3-(4-fluorophenyl)-2-((5-methyl-3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-3-oxopropionate(6.50 g, 15.1 mmol) in diethyl ether (50 ml) was added to the filtrate.The mixture was stirred at room temperature for 30 min. and 1Nhydrochloric acid was added to the reaction solution under ice-coolingto quench the reaction. Then, water (200 ml) was added and the mixturewas extracted with ethyl acetate (300 ml×2). The extract was washed withwater and saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1) to giveethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((5-methyl-3-(1,1,22-tetrafluoroethoxy)phenyl)methyl)propionate (6.56 g, 100%) as acolorless oil.

IR ν max^(KBr)cm⁻¹: 1715, 1605, 1512. Anal. Calcd for C₂₁H₂₁F₅O₄.0.3H₂O:C, 57.62; H, 4.97 Found: C, 57.54; H, 4.85. ¹H-NMR (CDCl₃)δ: 0.94 (3H,t, J=7.0 Hz), 2.29 (3H, s), 2.92-3.02 (4H, m), 3.89 (2H, q, J=7.0 Hz),5.00 (1H, s), 5.86 (1H, tt, J=53.0, 3.0 Hz), 6.72-6.86 (3H, m),7.00-7.10 (2H, m), 7.30-7.42 (2H, m).

3) To a solution ofethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((5-methyl-3-(1,1,2,2-trifluoroethoxy)phenyl)methyl)propionate(6.30 g, 14.6 mmol) in methanol (50 ml) was added 2N aqueous sodiumhydroxide solution (14.6 ml, 29.2 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid, and the mixture was extracted with ethyl acetate(100 ml×2). The extract was washed with water and saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was recrystallized from diethyl ether-hexane to give(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((5-methyl-3-(1,1,2,2-trifluoroethoxy)phenyl)methyl)propionicacid (6.0 g, 100%).

mp 82-83° C. IR ν max^(KBr)cm⁻¹: 1713, 1607, 1512. Anal. Calcd forC₁₉H₁₇F₅O₄: C, 56.19; H, 4.26 Found: C, 56.05; H, 4.13. ¹H-NMR (CDCl₃)δ:2.27 (3H, s), 2.80-3.08 (3H, m), 5.06 (1H, d, J=4.0 Hz), 5.86 (1H, tt,J=53.0, 2.8 Hz), 6.76 (2H, d, J=6.6 Hz), 6.84 (1H, s), 6.98-7.12 (2H,m), 7.30-7.42 (2H, m).

4) To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((5-methyl-3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionicacid (5.8 g, 14.3 mmol) in tetrahydrofuran (100 ml) were addeddiphenylphosphoryl azide (3.4 ml, 15.8 mmol) and triethylamine (3.0 ml,21.5 mmol), and the mixture was heated under reflux for 30 min. Thereaction solution was allowed to cool and water (200 ml) was added. Themixture was extracted with ethyl acetate (200 ml×2). The extract waswashed successively with 1N hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=1:1) andrecrystallized from ethyl acetate-hexane to give(4RS,5SR)-5-(4-fluorophenyl)-4-((5-methyl-3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidin-2-one(4.1 g, 71%).

mp 107-108° C. IR ν max^(KBr)cm⁻¹: 1761, 1611, 1597, 1514. Anal. Calcdfor C₁₉H₁₆F₅NO₃: C, 56.86; H, 4.02; N, 3.49. Found: C, 56.64; H, 4.01;N, 3.58. ¹H-NMR (CDCl₃)δ: 1.16-2.40 (2H, m), 2.32 (3H, s), 4.18-4.32(1H, m), 5.12 (1H, brs), 5.79 (1H, d, J=7.8 Hz), 5.89 (1H, tt, J=53.0,3.0 Hz), 6.70 (2H, d, J=8.0 Hz), 6.91. (1H, s), 7.04-7.20 (2H, m),7.30-7.42 (2H, m).

5) To a solution of(4RS,5SR)-5-(4-fluorophenyl)-4-((5-methyl-3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-1,3-oxazolidin-2-one(3.0 g, 7.48 mmol) in ethanol (30 ml) was added 8N aqueous sodiumhydroxide solution (4.7 ml, 37.4 mmol), and the mixture was heated underreflux for 3 hrs. The reaction solution was concentrated, diluted withwater (100 ml) and extracted with ethyl acetate (100 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. The residue was recrystallizedfrom ethyl acetate-hexane to give(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(5-methyl-3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol(2.34 g, 83%).

mp 96-98° C. IR ν max^(KBr)cm⁻¹: 1617, 1595, 1508, 1458. Anal. Calcd forC₁₈H₁₈F₅NO₂: C, 57.60; H, 4.83; N, 3.73. Found: C, 57.59; H, 4.79; N,3.73. ¹H-NMR (CDCl₃)δ: 2.20-2.50 (1H, m), 2.32 (3H, s), 2.76 (1H, dd,J=13.4, 3.2 Hz), 3.20-3.32 (1H, m), 4.65 (1H, d, J=4.8 Hz), 5.88 (1H,tt, J=53.0, 3.0 Hz), 6.80 (1H, s), 6.82-6.90 (2H, m), 7.00-7.12 (2H, m),7.30-7.42 (2H, m).

6) To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(5-methyl-3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol(197 mg, 0.53 mmol) in acetonitrile (20 ml) were added4-fluoronaphthalenecarboxylic acid (100 mg, 0.53 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg,0.79 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol), and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure.Recrystallization of the residue from ethyl acetate-hexane gave thetitle compound (234 mg, 81%).

mp 189-190° C. IR ν max^(KBr)cm⁻¹: 1642, 1626, 1601, 1512. Anal. Calcdfor C₂₉H₂₃F₆NO₃.0.1H₂O: C, 63.41; H, 4.25; N, 2.55. Found: C, 63.22; H,4.24; N, 2.77. ¹H-NMR (CDCl₃)δ: 2.29 (3H, s), 2.77 (1H, dd, J=14.0, 11.0Hz), 3.00 (1H, dd, J=14.0, 4.0 Hz), 4.62-4.82 (1H, m), 5.07 (1H, d,J=3.6 Hz), 5.87 (1H, tt, J=53.0, 3.0 Hz), 5.95 (1H, d, J=8.8 Hz),6.80-7.20 (7H, m), 7.38-7.60 (4H, m), 7.80 (1H, d, J=8.0 Hz), 8.08 (1H,d, J=7.6 Hz).

Example 231N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((5-methyl-3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-1-(2-fluorophenyl)-3-(5-methyl-3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol(200 mg, 0.53 mmol) in acetonitrile (20 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (100 mg, 0.53mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153mg, 0.80 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with 1Nhydrochloric acid, 1N aqueous sodium hydroxide solution and saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. Recrystallization of the residue from ethylacetate-hexane gave the title compound (228 mg, 78%).

mp 175-176° C. IR ν max^(KBr)cm⁻¹: 1636, 1510, 1449. ¹H-NMR (CDCl₃)δ:1.90-2.10 (2H, m), 2.10-2.28 (2H, m), 2.31 (3H, s), 2.60-2.82 (3H, m),3.87 (1H, brs), 4.56-4.72 (1H, m), 5.01 (1H, d, J=3.8 Hz), 5.76 (1H, d,J=8.4 Hz), 5.87 (1H, tt, J=53.0, 3.0 Hz), 5.90-6.00 (1H, m), 6.22 (1H,d, J=11.6 Hz), 6.82 (1H, s), 6.84-7.20 (7H, m), 7.36-7.50 (2H, m).

Example 232N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-chloro-3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethyl)-4-fluoro-1-naphthalenecarboxamide

1) To a solution of 4-chloro-3-(1,1,2,2-tetrafluoropropyloxy)toluene(7.63 g, 28.3 mmol, 90% purity) in carbon tetrachloride (100 ml) wereadded N-bromosuccinimide (5.54 g, 31.1 mmol) and2,2′-azobis(isobutyronitrile) (255 mg, 1.56 mmol), and the mixture washeated under reflux overnight. Insoluble material was filtered off withcelite, and the filtrate was concentrated to give a bromo form. To asolution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (5.35 g, 25.5 mmol)in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60% in oil,1.02 g, 25.5 mmol) under ice-cooling, and the mixture was stirred atroom temperature for 30 min. To the reaction solution was dropwise addeda solution of the bromo form synthesized earlier in 1,2-dimethoxyethane(20 ml), and the mixture was stirred at room temperature for 1 hr. Thereaction solution was poured into water (200 ml), and extracted withethyl acetate (200 ml×2). The extract was washed with water andsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (toluene:hexane=1:1-ethyl acetate). Recrystallizationfrom ethyl acetate-hexane gave ethyl2-((4-chloro-3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-3-(4-fluorophenyl)-3-oxopropionate(6.71 g, 56%).

mp 73-74° C. IR ν max^(KBr)cm⁻¹: 1738, 1688, 1599. Anal. Calcd forC₂₀H₁₆ClF₅O₄: C, 53.29; H, 3.58 Found: C, 53.38; H, 3.35. ¹H-NMR(CDCl₃)δ: 1.13 (3H, t, J=7.0 Hz), 3.32 (2H, d, J=7.2 Hz), 4.11 (2H, q,J=7.0 Hz), 4.54 (1H, t, J=7.2 Hz), 5.97 (1H, tt, J=53.2, 3.0 Hz),7.06-7.40 (5H, m), 7.92-8.08 (2H, m).

2) To a solution of zinc chloride (4.0 g, 29.3 mmol) in diethyl ether(100 ml) was added sodium borohydride (2.22 g, 58.6 mmol), and themixture was stirred at room temperature for 30 min. Insoluble materialwas filtered off, and a solution of ethyl2-((4-chloro-3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-3-(4-fluorophenyl)-3-oxopropionate(6.60 g, 14.6 mmol) in diethyl ether (50 ml) was added to the filtrate.The mixture was stirred at room temperature for 30 min. and 1Nhydrochloric acid was added to the reaction solution under ice-coolingto quench the reaction. Then, water (200 ml) was added and the mixturewas extracted with ethyl acetate (300 ml×2). The extract was washed withwater and saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1) to giveethyl(2RS,3RS)-2-((4-chloro-3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-3-(4-fluorophenyl)-3-hydroxypropionate(5.85 g, 88%) as a colorless oil.

IR ν max^(KBr)cm⁻¹: 1717, 1605, 1510, 1487. Anal. Calcd forC₂₀H₁₈ClF₅O₄: C, 53.05; H, 4.01 Found: C, 53.17; H, 4.13. ¹H-NMR(CDCl₃)δ: 0.95 (3H, t, J=7.0 Hz), 2.84-3.04 (4H, m), 3.89 (2H, q, J=7.0Hz), 4.98-5.06 (1H, m), 5.96 (1H, tt, J=53.0, 3.4 Hz), 6.92-7.10 (4H,m), 7.30-7.44 (3H, m).

3) To a solution ofethyl(2RS,3RS)-2-((4-chloro-3-(1,1,2,2-trifluoroethoxy)phenyl)methyl)-3-(4-fluorophenyl)-3-hydroxypropionate(5.60 g, 12.37 mmol) in methanol (50 ml) was added 2N aqueous sodiumhydroxide solution (12.3 ml, 24.6 mmol), and the mixture was stirredovernight at room temperature. After the reaction solution was acidifiedwith 1N hydrochloric acid, the mixture was extracted with ethyl acetate(100 ml×2). The extract was washed with water and saturated brine, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was recrystallized from diethyl ether-hexane to give(2RS,3RS)-2-((4-chloro-3-(1,1,2,2-trifluoroethoxy)phenyl)methyl)-3-(4-fluorophenyl)-3-hydroxypropionicacid (4.12 g, 78%).

mp 121-122° C. IR ν max^(KBr)cm⁻¹: 1713, 1607, 1512, 1489. Anal. Calcdfor C₁₈H₁₄ClF₅O₄: C, 50.90; H, 3.32 Found: C, 50.92; H, 3.07. ¹H-NMR(CDCl₃)δ: 2.90-3.06 (3H, m), 5.07 (1H, s), 5.96 (1H, tt, J=53.0, 3.2Hz), 6.94 (1H, dd, J=8.2, 2.0 Hz), 7.00-7.12 (3H, m), 7.24-7.40 (3H, m).

4) To a solution of(2RS,3RS)-2-((4-chloro-3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-3-(4-fluorophenyl)-3-hydroxypropionicacid (2.0 g, 4.71 mmol) in tetrahydrofuran (40 ml) were addeddiphenylphosphoryl azide (1.12 ml, 5.18 mmol) and triethylamine (0.99ml, 7.07 mmol), and the mixture was heated under reflux for 3 hrs. Thereaction solution was allowed to cool and water (200 ml) was added. Themixture was extracted with ethyl acetate (200 ml×2). The extract waswashed successively with 1N hydrochloric acid, saturated aqueous sodiumhydrogen carbonate solution and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=1:1)to give(4RS,5SR)-4-((4-chloro-3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-5-(4-fluorophenyl)-1,3-oxazolidin-2-one(1.72 g, 87%) as a colorless oil. IR ν max^(KBr)cm⁻¹: 1759, 1514, 1489.Anal. Calcd for C₁₈H₁₃ClF₅NO₃: C, 51.26; H, 3.11; N, 3.32. Found: C,51.16; H, 3.13; N, 3.24. ¹H-NMR (CDCl₃)δ: 2.30 (2H, d, J=6.8 Hz), 4.25(1H, q, J=6.8 Hz), 5.30 (1H, brs), 5.80 (1H, d, J=8.0 Hz), 5.98 (1H, tt,J=53.0, 3.0 Hz), 6.89 (1H, dd, J=8.0, 2.0 Hz), 6.99 (1H, s), 7.06-7.20(2H, m), 7.30-7.42 (3H, m).

5) To a solution of(4RS,5SR)-4-((4-chloro-3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-5-(4-fluorophenyl)-1,3-oxazolidin-2-one(1.42 g, 3.37 mmol) in ethanol (20 ml) was added 8N aqueous sodiumhydroxide solution (2.1 ml, 16.9 mmol), and the mixture was heated underreflux for 3 hrs. The reaction solution was concentrated, diluted withwater (100 ml) and extracted with ethyl acetate (100 ml×2). The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. The residue was recrystallizedfrom ethyl acetate-hexane to give(1RS,2SR)-2-amino-3-(4-chloro-3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-1-propanol(1.17 g, 88%).

mp 109-110° C. IR ν max^(KBr)cm⁻¹: 1605, 1508, 1489. Anal. Calcd forC₁₇H₁₅ClF₅NO₂: C, 51.59; H, 3.82; N, 3.54. Found: C, 51.62; H, 3.78; N,3.55. ¹H-NMR (CDCl₃)δ: 2.39 (1H, dd, J=14.0, 10.0 Hz), 2.81 (1H, dd,J=14.0, 3.4 Hz), 3.18-3.32 (1H, m), 4.63 (1H, d, J=5.2 Hz), 5.98 (1H,tt, J=53.0, 3.0 Hz), 7.00-7.20 (4H, m), 7.30-7.44 (3H, m).

6) To a solution of(1RS,2SR)-2-amino-3-(4-chloro-3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-1-propanol(208 mg, 0.53 mmol) in acetonitrile (20 ml) were added4-fluoronaphthalenecarboxylic acid (100 mg, 0.53 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg,0.79 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol), and themixture was stirred overnight at room temperature. The reaction solutionwas diluted with water (100 ml) and extracted with ethyl acetate (100ml×2). The extract was washed successively with 1N hydrochloric acid, 1Naqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate and evaporated under reduced pressure.Recrystallization of the residue from ethyl acetate-hexane gave thetitle compound (273 mg, 91%).

mp 206-207° C. IR ν max^(KBr)cm⁻¹: 1642, 1626, 1601, 1512. ¹H-NMR(CDCl₃)δ: 2.84 (1H, dd, J=14.2, 10.6 Hz), 3.02 (1H, dd, J=14.2, 4.2 Hz),4.68-4.84 (1H, m), 5.07 (1H, d, J=4.0 Hz), 5.95 (1H, tt, J=53.0, 3.0Hz), 5.99 (1H, d, J=9.0 Hz), 6.92-7.30 (6H, m), 7.30-7.60 (5H, m), 7.73(1H, d, J=8.2 Hz), 8.08 (1H, d, J=8.2 Hz)

Example 233N-((1RS,2SR)-1-((4-chloro-3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethyl)-2-(4-fluorophenyl)-2-hydroxy-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-3-(4-chloro-3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(2-fluorophenyl)-1-propanol(210 mg, 0.53 mmol) in acetonitrile (20 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (100 mg, 0.53mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153mg, 0.80 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with 1Nhydrochloric acid, 1N aqueous sodium hydroxide solution and saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. Recrystallization of the residue from ethylacetate-hexane gave the title compound (213 mg, 71%).

mp 174-175° C. IR ν max^(KBr)cm⁻¹: 1640, 1508, 1489. ¹H-NMR (CDCl₃)δ:1.90-2.10 (2H, m), 2.12-2.26 (2H, m), 2.60-2.72 (2H, m), 2.78 (1H, dd,J=14.6, 10.4 Hz), 2.96 (1H, dd, J=14.6, 4.4 Hz), 3.40 (1H, brs),4.58-4.72 (1H, m), 5.01 (1H, d, J=4.0 Hz), 5.80 (1H, d, J=8.8 Hz),5.82-5.98 (1H, m), 5.95 (1H, tt, J=53.0, 3.0 Hz), 6.16 (1H, d, J=11.6Hz), 6.92-7.20 (7H, m), 7.32-7.50 (3H, m).

Example 234N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-((4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1) To a solution of lithium aluminum hydride (1.02 g, 26.8 mmol) intetrahydrofuran (100 ml) was added a solution of ethyl4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)benzoate (5.0 g, 17.8 mmol) intetrahydrofuran (20 ml) under ice-cooling. After the reaction solutionwas stirred at room temperature for 30 min., 1N aqueous sodium hydroxidesolution (20 ml) was added, and the mixture was filtered with celite.The filtrate was concentrated and water was added. The mixture wasextracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure to give(4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methanol (4.45 g,100%) as a colorless oil.

¹H-NMR (CDCl₃)δ: 2.27 (3H, s), 4.67 (2H, s), 5.94 (1H, tt, J=53.0,2.6,Hz), 7.14-7.28 (3H, m). IR ν max^(KBr)cm⁻¹: 1584, 1508, 1456, 1418.Anal. Calcd for C₁₀H₁₀F₄O₂: C, 50.43; H, 4.23 Found: C, 50.44; H, 4.18.

2) To a solution of(4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methanol (4.26 g, 17.9mmol) in ethyl acetate (60 ml) were added methanesulfonyl chloride (2.25g, 19.7 mmol) and triethylamine (3.0 ml, 21.5 mmol) at 0° C., and themixture was stirred for 30 min. Insoluble material was filtered off, andthe filtrate was concentrated to give a mesyl form. To a solution ofethyl 3-(4-fluorophenyl)-3-oxopropionate (3.76 g, 17.9 mmol) in1,2-dimethoxyethane (40 ml) was added sodium hydride (60% in oil, 0.72g, 17.9 mmol) under ice-cooling, and the mixture was stirred at roomtemperature for 30 min. To the reaction solution was dropwise added asolution of the mesyl form synthesized earlier in 1,2-dimethoxyethane(20 ml), and the mixture was stirred overnight at room temperature. Thereaction solution was poured into water (200 ml), and extracted withethyl acetate (200 ml×2). The extract was washed with water andsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (toluene) and recrystallized from hexane to give ethyl3-(4-fluorophenyl)-2-((4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)-3-oxopropionate(4.91 g, 64%).

¹H-NMR (CDCl₃)δ: 1.13 (3H, t, J=7.0 Hz), 2.21 (3H, s), 3.30 (2H, d,J=7.4 Hz), 4.10 (2H, q, J=7.0 Hz), 4.54 (1H, t, J=7.4 Hz), 5.92 (1H, tt,J=53.0, 2.8 Hz), 7.00-7.20 (5H, m), 7.94-8.04 (2H, m). IR νmax^(KBr)cm⁻¹: 1736, 1688, 1599, 1508, 1447, 1412. mp 52-53° C. Anal.Calcd for C₂₁H₁₉F₅O₄: C, 58.61; H, 4.45 Found: C, 58.61; H, 4.55.

3) To a solution of zinc chloride (3.04 g, 22.3 mmol) in diethyl ether(70 ml) was added sodium borohydride (1.69 g, 44.6 mmol), and themixture was stirred at room temperature for 30 min. Insoluble materialwas filtered off and a solution of ethyl3-(4-fluorophenyl)-2-((4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)-3-oxopropionate(4.8 g, 11.2 mmol) in diethyl ether (50 ml) was added to the filtrate.The mixture was stirred at room temperature for 30 min. and 1Nhydrochloric acid was added to the reaction solution under ice-coolingto quench the reaction. Then, water (100 ml) was added and the mixturewas extracted with ethyl acetate (200 ml×2). The extract was washed withwater and saturated brine, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1) to give ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionate(4.69 g, 97%) as a colorless oil.

¹H-NMR (CDCl₃)δ: 0.94 (3H, t, J=7.4 Hz), 2.21 (3H, s), 2.80-3.10 (3H,m), 3.89 (2H, q, J=7.4 Hz), 4.96-5.02 (1H, m), 5.92 (1H, tt, J=52.2, 2.6Hz), 6.86-7.12 (5H, m), 7.30-7.42 (2H, m). IR ν max^(KBr)cm⁻¹: 1717,1605, 1580, 1510, 1447. Anal. Calcd for C₂₁H₂₁F₅O₄: C, 58.33; H, 4.90Found: C, 58.29; H, 4.88.

4) To a solution ofethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionate(4.5 g, 10.4 mmol) in methanol (20 ml) was added 2N aqueous sodiumhydroxide solution (10.4 ml, 20.8 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). Theextract was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wasrecrystallized from diethyl ether-hexane to give(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionicacid (3.56 g, 85%).

¹H-NMR (CDCl₃)δ: 2.21 (3H, s), 2.80-3.02 (3H, m), 5.04 (1H, d, J=3.8Hz), 5.90 (1H, tt, J=53.0, 2.6 Hz), 6.84-7.12 (5H, m), 7.30-7.40 (2H,m), IR ν max^(KBr)cm⁻¹: 1713, 1607, 1510, 1449, 1422. mp 102-103° C.Anal. Calcd for C₁₉H₁₇F₅O₄: C, 56.44; H, 4.24 Found: C, 56.56; H, 4.20.

5) To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionicacid (3.3 g, 8.16 mmol) in tetrahydrofuran (60 ml) were addeddiphenylphosphoryl azide (1.93 ml, 8.98 mmol) and triethylamine (1.71ml, 12.2 mmol), and the mixture was heated under reflux for 2 hrs. Thereaction solution was allowed to cool and water (200 ml) was added. Themixture was extracted with ethyl acetate (100 ml×2). The extract waswashed successively with 1N hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate). Recrystallizationfrom ethyl acetate-hexane gave(4RS,5SR)-5-(4-fluorophenyl)-4-((4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)-1,3-oxazolidin-2-one(2.97 g, 91%).

¹H-NMR (CDCl₃)δ: 2.23 (3H, s), 2.12-2.30 (2H, m), 4.18-4.30 (1H, m),5.21 (1H, s), 5.78 (1H, d, J=8.0 Hz), 5.93 (1H, tt, J=53.0, 2.6 Hz),6.80-6.90 (2H, m), 7.04-7.20 (3H, m), 7.30-7.42 (2H, m). IR νmax^(KBr)cm⁻¹: 1759, 1609, 1580, 1514, 1422. mp 112-113° C. Anal. Calcdfor C₁₉H₁₆F₅NO₃: C, 56.86; H, 4.02; N, 3.49. Found: C, 56.87; H, 3.91;N, 3.59.

6) To a solution of(4RS,5SR)-5-(4-fluorophenyl)-4-((4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)-1,3-oxazolidin-2-one(2.7 g, 6.73 mmol) in ethanol (10 ml) was added 8N aqueous sodiumhydroxide solution (4.2 ml, 33.6 mmol), and the mixture was heated underreflux for 4 hrs. The reaction solution was concentrated, diluted withwater (100 ml), and the mixture was extracted with ethyl acetate (100ml×2). The extract was washed with saturated brine, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue-wasrecrystallized from ethyl acetate-hexane to give(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)-1-propanol(2.25 g, 89%).

¹H-NMR (CDCl₃)δ: 2.24 (3H, s), 2.33 (1H, dd, J=14.0, 10.6 Hz), 2.77 (1H,dd, J=14.0, 3.2 Hz), 3.20-3.32 (1H, m), 4.65 (1H, d, J=4.8 Hz), 5.93(1H, tt, J=53.0, 3.0 Hz), 6.92-7.18 (5H, m), 7.30-7.42 (2H, m). IR νmax^(KBr)cm⁻¹: 1605, 1582, 1508. mp 112-113° C. Anal. Calcd forC₁₈H₁₈F₅NO₂: C, 57.60; H, 4.83; N, 3.73. Found: C, 57.59; H, 4.75; N,3.73.

7) To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-methyl-3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)-1-propanol(300 mg, 0.80 mmol) in acetonitrile (20 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (150 mg, 0.80mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230mg, 1.20 mmol) and 1-hydroxy-1H-benzotriazole (123 mg, 0.80 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with 1Nhydrochloric acid, 1N aqueous sodium hydroxide solution and saturatedbrine, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. Recrystallization of the residue from ethylacetate-hexane gave the title compound (363 mg, 83%).

1H-NMR (CDCl₃)δ: 1.90-2.08 (2H, m), 2.12-2.30 (2H, m), 2.24 (3H, s),2.60-2.80 (3H, m), 2.95 (1H, dd, J=15.0, 4.0 Hz), 4.60-4.76 (1H, m),5.00 (1H, d, J=3.6 Hz), 5.60-6.24 (4H, m), 6.94-7.20 (8H, m), 7.38-7.48(2H, m). IR ν max^(KBr)cm⁻¹: 1640, 1607, 1508, 1447, 1424. mp 168-169°C. Anal. Calcd for C₃₀H₂₈F₅NO₃.0.1H₂O: C, 65.83; H, 5.19; N, 2.56.Found: C, 65.60; H, 4.89; N, 2.82.

Example 235N-((1RS,2SR)-2-(3-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl)-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

1) ethyl3-(3-fluorophenyl)-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate

To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (8.91 g, 42.8mmol) in ethyl acetate (100 ml) were added N-bromosuccinimide (8.35 g,46.9 mmol) and 2,2′-azobis(isobutyronitrile) (335 mg, 2.04 mmol), andthe mixture was heated under reflux for 5 hrs. The reaction solution wasconcentrated and the crystals were filtered with hexane. The filtratewas concentrated to prepare3-(1,1,2,2-tetrafluoroethoxy)-a-bromotoluene. To a solution of ethyl3-(3-fluorophenyl)-3-oxopropanoate (8.57 g, 40.8 mmol) in1,2-dimethoxyethane (80 ml) was added sodium hydride (60% in oil, 1.63g, 40.8 mmol) under ice-cooling, and the mixture was stirred at roomtemperature for 30 min. To the reaction solution was dropwise added asolution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene preparedearlier in 1,2-dimethoxyethane (10 ml), and the mixture was stirredovernight at room temperature. The reaction solution was poured intowater (100 ml), and the mixture was extracted with ethyl acetate (100ml×2). The extract was washed with water and saturated brine, dried(anhydrous magnesium sulfate), and evaporated under reduced pressure.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=10:1-6:1) and recrystallized from ethylacetate-hexane to give the objective substance (8.86 g, 52%).

¹H-NMR (CDCl₃)δ: 1.12 (3H, t, J=7.2 Hz), 3.33 (2H, d, J=7.5 Hz),4.02-4.18 (2H, m), 4.54 (1H, t, J=7.2 Hz), 5.89 (1H, tt, J=53.1, 2.7Hz), 7.02-7.10 (2H, m), 7.14 (1H, d, J=7.8 Hz), 7.26-7.32 (2H, m),7.38-7.48 (1H, m), 7.60-7.68 (1H, m), 7.72 (1H, d, J=7.8 Hz). IR νmax^(KBr)cm⁻¹: 1738, 1694, 1613, 1590, 1487, 1445. mp 52-53° C. Anal.Calcd for C₂₀H₁₇O₄F₅: C, 57.70; H, 4.12 Found: C, 57.72; H, 4.13.

2)ethyl(2RS,3RS)-3-(3-fluorophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate

To a solution of zinc chloride (5.60 g, 41.1 mmol) in diethyl ether (140ml) was added sodium borohydride (3.11 g, 82.2 mmol), and the mixturewas stirred at room temperature for 30 min. Insoluble material wasfiltered off. To the filtrate was added a solution of ethyl3-(3-fluorophenyl)-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate(8.56 g, 20.6 mmol) in diethyl ether (50 ml) at 0° C., and the mixturewas stirred for 30 min. 1N Hydrochloric acid was added to the reactionsolution to stop the reaction. Then, water (100 ml) was added and themixture was extracted with ethyl acetate (200 ml×2). The extract waswashed with water and saturated brine, dried (anhydrous magnesiumsulfate), and evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=4:1)to give the objective substance (7.04 g, 82%) as a colorless oil.

¹H-NMR (CDCl₃)δ: 0.95 (3H, t, J=7.0 Hz), 2.86-3.06 (3H, m), 3.10 (1H, d,J=3.0 Hz), 3.92 (2H, q, J=7.0 Hz), 5.06 (1H, s), 5.88 (1H, tt, J=53.0,3.0 Hz), 6.90-7.08. (4H, m), 7.10-7.40 (4H, m).

IR ν max^(KBr)cm⁻¹: 1724, 1715, 1614, 1591, 1489, 1451. Anal. Calcd forC₂₀H₁₉O₄F₅: C, 57.42; H, 4.58 Found: C, 57.36; H, 4.55.

3)(2RS,3RS)-3-(3-fluorophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoicacid

To a solution ofethyl(2RS,3RS)-3-(3-fluorophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate(6.92 g, 16.5 mmol) in methanol (50 ml) was added 2N aqueous sodiumhydroxide solution (16.5 ml, 33.0 mmol), and the mixture was stirred atroom temperature for 2 hrs. The reaction solution was acidified with 1Nhydrochloric acid and extracted with ethyl acetate (200 ml×2). Theextract was washed with water and saturated brine, dried (anhydrousmagnesium sulfate) and evaporated under reduced pressure.Recrystallization of the residue from ethyl acetate-hexane gave theobjective substance (4.28 g, 66%).

¹H-NMR (CDCl₃)δ: 2.80-3.16 (3H, m), 5.14 (1H, d, J=3.6 Hz), 5.90 (1H,tt, J=53.0, 3.0 Hz), 6.90-7.40 (8H, m). IR ν max^(KBr)cm⁻¹: 1713, 1615,1591, 1489, 1451. mp 116-117° C. Anal. Calcd for C₁₈H₁₅O₄F₅: C, 55.39;H, 3.87 Found: C, 55.42; H, 3.86.

4)(4RS,5SR)-5-(3-fluorophenyl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-(3-fluorophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoicacid (4.15 g, 10.6 mmol) in tetrahydrofuran (80 ml) were addeddiphenylphosphoryl azide (2.52 ml, 11.7 mmol) and triethylamine (2.23ml, 16.0 mmol), and the mixture was heated under reflux for 3 hrs. Thereaction solution was allowed to cool and water (200 ml) was added. Themixture was extracted with ethyl acetate (100 ml×2). The extract waswashed successively with 1N hydrochloric acid, aqueous sodium hydrogencarbonate and saturated brine, dried (anhydrous magnesium sulfate) andevaporated under reduced pressure. Recrystallization of the residue fromethyl acetate-hexane gave the objective substance (3.46 g, 84%).

¹H-NMR (CDCl₃)δ: 2.20-2.40 (2H, m), 4.20-4.30 (1H, m), 5.17 (1H, s),5.80 (1H, d, J=7.8 Hz), 5.90 (1H, tt, J=53.1, 2.7 Hz), 6.89 (1H, s),6.96 (1H, d, J=8.1 Hz), 7.04-7.20 (4H, m), 7.24-7.36 (1H, m), 7.36-7.46(1H, m). IR ν max^(KBr)cm⁻¹: 1767, 1615, 1593, 1489, 1453. mp 110-111°C. Anal. Calcd for C₁₈H₁₄NO₃F₅: C, 55.82; H, 3.64; N, 3.62. Found: C,55.81; H, 3.62; N, 3.58.

5)(1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol

To a solution of(4RS,5SR)-5-(3-fluorophenyl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one(3.30 g, 8.52 mmol) in ethanol (12 ml) was added 8N aqueous sodiumhydroxide solution (5.3 ml, 42 mmol), and the mixture was heated underreflux for 5 hrs. The reaction solutions was concentrated, diluted withwater (100 ml), and extracted with ethyl acetate (100 ml×2). The extractwas washed with saturated brine, dried (anhydrous magnesium sulfate) andevaporated under reduced pressure. The residue was recrystallized fromdiisopropyl ether-hexane to give the objective substance (2.60 g, 84%).

¹H-NMR (CDCl₃)δ: 1.85 (2H, brs), 2.38 (1H, dd, J=13.8, 10.6 Hz), 2.77(1H, dd, J=13.8, 3.4 Hz), 3.24-3.36 (1H, m), 4.69 (1H, d, J=4.8 Hz),5.89 (1H, tt, J=53.0, 3.0 Hz), 6.94-7.22 (5H, m), 7.22-7.40 (3H, m). IRν max^(KBr)cm⁻¹: 1613, 1590, 1487, 1449, 1304, 1279. mp 51-52° C. Anal.Calcd for C₁₇H₁₆NO₂F₅: C, 56.51; H, 4.46; N, 3.88. Found: C, 56.42; H,4.39; N, 3.72.

6)N-{(1RS,2SR)-2-(3-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(448 mg, 1.24 mmol) in acetonitrile (20 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (234 mg, 1.24mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (357mg, 1.86 mmol) and 1-hydroxybenzotriazole hydrate (190 mg, 1.24 mmol),and the mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with 1Nhydrochloric acid, 1N aqueous sodium hydroxide solution and saturatedbrine, dried (anhydrous magnesium sulfate) and evaporated under reducedpressure. Recrystallization of the residue from ethyl acetate-hexanegave the objective substance (444 mg, 67%).

¹H-NMR (CDCl₃)δ: 1.94-2.06 (2H, m), 2.16-2.24 (2H, m), 2.62-2.68 (2H,m), 2.79 (1H, dd, J=14.7, 10.8 Hz), 2.96 (1H, dd, J=14.7, 4.2 Hz),4.60-4.74 (1H, m), 5.07 (1H, d, J=3.3 Hz), 5.81 (1H, d, J=8.1 Hz), 5.88(1H, tt,=53.1, 3.0 Hz), 5.90-6.00 (1H, m), 6.23 (1H, d, J=11.7 Hz),6.94-7.40 (11H, m). IR ν max^(KBr)cm⁻¹: 1634, 1615, 1590, 1514, 1489,1451. mp 150-155° C. Anal. Calcd for C₂₉H₂₆NO₃F₅: C, 65.53; H, 4.93; N,2.64. Found: C, 65.25; H, 4.95; N, 2.66.

Example 236N-{(1RS,2SR)-2-[4-(benzyloxy)phenyl]-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

1) 4-benzyloxyacetophenone

To a solution of 4-hydroxyacetophenone (25 g, 184 mmol) in acetone (500ml) were added potassium carbonate (50.7 g, 367 mmol) and benzyl bromide(32 g, 187 mmol), and the mixture was stirred overnight at roomtemperature. The reaction solution was concentrated, diluted with water(500 ml) and extracted with ethyl acetate (500 ml×2). The extract waswashed successively with water and saturated brine, dried (anhydrousmagnesium sulfate) and evaporated under reduced pressure.Recrystallization of the residue from ethyl acetate-hexane gave theobjective substance (36.8 g, 89%).

¹H-NMR (CDCl₃)δ: 2.56 (3H, s), 5.13 (2H, s), 7.01 (2H, d, J=9.0 Hz),7.30-7.44 (5H, m), 7.94 (2H, d, J=9.0 Hz). IR ν max^(KBr)cm⁻¹: 1674,1601, 1576, 1508, 1454, 1420. mp 87-88° C. Anal. Calcd for C₁₅H₁₄O₂ C,79.62; H, 6.24 Found: C, 79.68; H, 6.23.

2) ethyl 3-[4-(benzyloxy)phenyl]-3-oxopropanoate

To a solution of 4-benzyloxyacetophenone (36 g, 159 mmol) in diethylcarbonate (200 ml) was added ethanol (0.6 ml) and sodium hydride (60% inoil, 12.7 g, 318 mmol) was added under ice-cooling. The mixture wasstirred at room temperature for 2 hrs. To the reaction solution wasadded 6N hydrochloric acid to stop the reaction, and water (500 ml) wasadded. Then, the mixture was extracted with ethyl acetate (500 ml×2).The extract was washed successively with water and saturated brine,dried (anhydrous magnesium sulfate) and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate) and recrystallized from ethyl acetate-hexane to give theobjective substance (49.3 g, 100%).

¹H-NMR (CDCl₃)δ: 1.26 (3H, t, J=7.2 Hz), 3.94 (2H, s), 4.21 (2H, q,J=7.2 Hz), 5.14 (2H, s), 6.98-7.06 (2H, m), 7.30-7.48 (5H, m), 7.88-7.96(2H, m). IR ν max^(KBr)cm⁻¹: 1740, 1678, 1601, 1576, 1510. mp 53-54° C.Anal. Calcd for C₁₈H₁₈O₄ C, 72.47; H, 6.08 Found: C, 72.56; H, 6.10.

3) ethyl3-[4-(benzyloxy)phenyl]-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate

To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (27.8 g, 133 mmol)in ethyl acetate (250 ml) were added N-bromosuccinimide (26.1 g, 147mmol) and 2,2′-azobis(isobutyronitrile) (440 mg, 2.67 mmol), and themixture was heated under reflux for 5 hrs. After concentration of thereaction solution, crystals were filtered with hexane and the filtratewas concentrated to give 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene.To a solution of ethyl 3-[4-(benzyloxy)phenyl]-3-oxopropanoate (37.8 g,127 mmol) in 1,2-dimethoxyethane (250 ml) was added sodium hydride (60%in oil, 5.07 g, 127 mmol) under ice-cooling, and the mixture was stirredat room temperature for 30 min. To the reaction solution was dropwiseadded a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotolueneprepared earlier in 1,2-dimethoxyethane (50 ml), and the mixture wasstirred overnight at room temperature. The reaction solution was pouredinto water (500 ml), and the mixture was extracted with ethyl acetate(500 ml×2). The extract was washed with water and saturated brine, dried(anhydrous magnesium sulfate) and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1-1:1) and recrystallized from ethyl acetate-hexane to givethe objective substance (43.4 g, 68%).

¹H-NMR (CDCl₃)δ: 1.12 (3H, t, J=7.0 Hz), 3.20-3.42 (2H, m), 4.09 (2H, q,J=7.0 Hz), 4.56 (1H, t, J=7.4 Hz), 5.12 (2H, s), 5.88 (1H, tt, J=53.0,3.0 Hz), 6.92-7.50 (11H, m), 7.88-8.00 (2H, m). IR ν max^(KBr)cm⁻¹:1732, 1680, 1601, 1576, 1510, 1454, 1422. mp 71-72° C. Anal. Calcd forC₂₇H₂₄O₅F₄ C, 64.28; H, 4.80 Found: C, 64.47; H, 4.78.

4)ethyl(2RS,3RS)-3-[4-(benzyloxy)phenyl]-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate

To a solution of zinc chloride (18.9 g, 139 mmol) in diethyl ether (500ml) was added sodium borohydride (10.5 g, 278 mmol), and the mixture wasstirred at room temperature for 30 min. Insoluble material was filteredoff. To the filtrate was added a solution of ethyl3-[4-(benzyloxy)phenyl]-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate(35.0 g, 69.4 mmol) in diethyl ether (200 ml) at 0° C., and the mixturewas stirred for 30 min. 1N Hydrochloric acid was added to the reactionsolution to stop the reaction. Then, water (500 ml) was added and themixture was extracted with ethyl acetate (500 ml×2). The extract waswashed with water and saturated brine, dried (anhydrous magnesiumsulfate) and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=4:1) andrecrystallized from ethyl acetate-hexane to give the objective substance(30.3 g, 86%).

¹H-NMR (CDCl₃)δ: 0.91 (3H, t, J=7.0 Hz), 2.77 (1H, d, J=2.8 Hz),2.90-3.08 (3H, m), 3.87 (2H, q, J=7.0 Hz), 4.92-5.00 (1H, m), 5.06 (2H,s), 5.88 (1H, tt, J=53.0, 3.0 Hz), 6.92-7.08 (5H, m), 7.20-7.50 (8H, m).IR ν max^(KBr)cm⁻¹: 1725, 1611, 1586, 1512, 1487, 1454. mp 67-68° C.Anal. Calcd for C₂₇H₂₆O₅F₄ C, 64.03; H, 5.17 Found: C, 64.02; H, 5.15.

5)(2RS,3RS)-3-[4-(benzyloxy)phenyl]-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoicacid

To a solution ofethyl(2RS,3RS)-3-[4-(benzyloxy)phenyl]-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate(25.0 g, 49.4 mmol) in methanol (200 ml) was added 2N aqueous sodiumhydroxide solution (49.0 ml, 98.0 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid and extracted with ethyl acetate (500 ml×2). Theextract was washed with water and saturated brine, dried (anhydrousmagnesium sulfate) and evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate).Recrystallization from ethyl acetate-hexane gave the objective substance(21 g, 89%).

¹H-NMR (CDCl₃)δ: 2.90-3.08 (3H, m), 5.02 (1H, d, J=3.9 Hz), 5.05 (2H,s), 5.86 (1H, tt, J=53.1, 3.0 Hz), 6.90-7.48 (13H, m). IR νmax^(KBr)cm⁻¹: 1709, 1611, 1586, 1512, 1489, 1454. mp 76-77° C. Anal.Calcd for C₂₅H₂₂O₅F₄ C, 62.76; H, 4.63 Found: C, 62.98; H, 4.57.

6)(4RS,5SR)-5-[4-(benzyloxy)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin2-one

To a solution of(2RS,3RS)-3-[4-(benzyloxy)phenyl]-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoicacid (21.0 g, 43.9 mmol) in tetrahydrofuran (300 ml) were addeddiphenylphosphoryl azide (10.4 ml, 48.3 mmol) and triethylamine (9.2 ml,65.9 mmol), ant the mixture was heated under reflux for 2 hrs. Thereaction solution was allowed to cool and water (400 ml) was added. Themixture was extracted with ethyl acetate (200 ml×2). The extract waswashed successively with 1N hydrochloric acid, aqueous sodium hydrogencarbonate and saturated brine, dried (anhydrous magnesium sulfate) andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=1:1). Recrystallizationfrom ethyl acetate-hexane gave the objective substance (16.4 g, 79%).

¹H-NMR (CDCl₃)δ: 2.22-2.40 (2H, m), 4.16-4.30 (1H, m), 5.08 (2H, s),5.25 (1H, s), 5.75 (1H, d, J=8.0 Hz), 5.89 (1H, tt, J=53.0, 3.0 Hz),6.80-7.50 (13H, m). IR ν max^(KBr)cm⁻¹: 1759, 1613, 1588, 1514, 1489,1454. mp 115-116° C. Anal. Calcd for C₂₅H₂₁NO₄F₄: C, 63.16; H, 4.45; N,2.95. Found: C, 62.89; H, 4.48; N, 2.75.

7)(1RS,2SR)-2-amino-1-[4-(benzyloxy)phenyl]-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol

To a solution of(4RS,5SR)-5-[4-(benzyloxy)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one(2.50 g, 5.26 mmol) in ethanol (30 ml) was added 8N aqueous sodiumhydroxide solution (2 ml, 16 mmol), and the mixture was heated underreflux for 5 hrs. The reaction solution was concentrated and dilutedwith water (100 ml). The mixture was extracted with ethyl acetate (100ml×2). The extract was washed with saturated brine, dried (anhydrousmagnesium sulfate) and evaporated under reduced pressure to give theobjective substance (2.4 g, 100%)

¹H-NMR (CDCl₃)δ: 1.69 (2H, brs), 2.40 (1H, dd, J=13.8, 10.2 Hz), 2.90(1H, dd, J=13.8, 3.0 Hz), 3.22-3.30 (1H, m), 4.59 (1H, d, J=5.4 Hz),5.08 (2H, s), 5.89 (1H, tt, J=53.1, 3.0 Hz), 6.96-7.10 (5H, m),7.26-7.50 (8H, m). IR ν max^(KBr)cm⁻¹: 1611, 1586, 1510, 1487, 1454.Anal. Calcd for C₂₄H₂₃NO₃F₄: C, 64.14; H, 5.16; N, 3.12. Found: C,63.87; H, 5.20; N, 2.96.

8)N-{(1RS,2SR)-2-[4-(benzyloxy)phenyl]-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-1-[4-(benzyloxy)phenyl]-3-[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]propan-1-ol(617 mg, 1.37 mmol) in acetonitrile (20 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (258 mg, 1.37mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (394mg, 2.06 mmol) and 1-hydroxybenzotriazole hydrate (210 mg, 1.37 mmol),and the mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with 1Nhydrochloric acid, 1N aqueous sodium hydroxide solution and saturatedbrine, dried (anhydrous magnesium sulfate) and evaporated under reducedpressure. Recrystallization of the residue from ethyl acetate-hexanegave the objective substance (474 mg, 56%).

¹H-NMR (CDCl₃)δ: 1.94-2.04 (2H, m), 2.12-2.24 (2H, m), 2.62-2.70 (2H,m), 2.78 (1H, dd, J=14.7, 10.5 Hz), 3.02 (1H, dd, J=14.7, 4.2 Hz), 3.40(1H, brs), 4.64-4.76 (1H, m), 4.97 (1H, d, J=3.9 Hz), 5.07 (2H, s), 5.72(1H, d, J=9.9 Hz), 5.70-6.08 (2H, m), 6.19 (1H, d, J=11.7 Hz), 6.92-7.18(8H, m), 7.26-7.48 (8H, m). IR ν max^(KBr)cm⁻¹: 1644, 1613, 1586, 1510,1454. mp 115-116° C. Anal. Calcd for C₃₆H₃₃NO₄F₄.0.1H₂O: C, 69.58; H,5.38; N, 2.25. Found: C, 69.45; H, 5.40; N, 2.27.

Example 237N-{(1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

1) ethyl 3-(3-chlorophenyl)-3-oxopropanoate

To a solution of 3-chloroacetophenone (23.9 g, 154 mmol) in diethylcarbonate (150 ml) was added ethanol (0.3 ml), and sodium hydride (60%in oil, 12.4 g, 309 mmol) was added under ice-cooling. The mixture wasstirred at room temperature for 2 hrs. To the reaction solution wasadded 6N hydrochloric acid to stop the reaction, and water (500 ml) wasadded. Then, the mixture was extracted with ethyl acetate (500 ml×2).The extract was washed successively with water and saturated brine,dried (anhydrous magnesium sulfate) and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=50:1-5:1) to give the objective substance (24.8 g,71%).

¹H-NMR (CDCl₃)δ: 1.20-1.40 (3H, m), 3.97 (2H×3/4, s), 4.16-4.32 (2H, m),5.65 (1H×1/4, s), 7.30-7.50 (1H, m), 7.54-7.68 (1H, m), 7.76-7.84 (1H,m), 7.90-7.96 (1H, m). IR ν max^(KBr)cm⁻¹: 1740, 1694, 1651, 1628, 1568,1474. Anal. Calcd for C₁₁H₁₁O₃Cl: C, 58.29; H, 4.89 Found: C, 58.54; H,4.84.

2) ethyl3-(3-chlorophenyl)-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate

To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (10.2 g, 49.0mmol) in ethyl acetate (80 ml) were added N-bromosuccinimide (9.6 g,53.9 mmol) and 2,2′-azobis(isobutyronitrile) (161 mg, 0.98 mmol), andthe mixture was heated under reflux for 5 hrs. The reaction solution wasconcentrated and crystals were filtered with hexane. The filtrate wasconcentrated to give 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To asolution of ethyl 3-(3-chlorophenyl)-3-oxopropanoate (10.0 g, 44.1 mmol)in 1,2-dimethoxyethane (100 ml) was added sodium hydride (60% in oil,1.76 g, 44.1 mmol) under ice-cooling, and the mixture was stirred atroom temperature for 30 min. To the reaction solution was dropwise addeda solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene preparedearlier in 1,2-dimethoxyethane (50 ml), and the mixture was stirredovernight at room temperature. The reaction solution was poured intowater (300 ml), and the mixture was extracted with ethyl acetate (300ml×2). The extract was washed with water and saturated brine, dried(anhydrous magnesium sulfate) and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1-1:1) to give the objective substance (7.5 g, 39%).

¹H-NMR (CDCl₃)δ: 1.13 (3H, t, J=7.2 Hz), 3.33 (2H, d, J=7.4 Hz),4.02-4.20 (2H, m), 4.54 (1H, t, J=7.2 Hz), 5.89 (1H, tt, J=53.0, 3.0Hz), 7.00-7.20 (2H, m), 7.20-7.46 (2H, m), 7.50-7.60 (1H, m), 7.78-7.84(1H, m), 7.90-7.98 (1H, m). IR ν max^(KBr)cm⁻¹: 1738, 1694, 1613, 1588,1572.

3) ethyl(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate

To a solution of zinc chloride (4.66 g, 34.2 mmol) in diethyl ether (100ml) was added sodium borohydride (2.59 g, 68.4 mmol), and the mixturewas stirred at room temperature for 30 min. Insoluble material wasfiltered off, and a solution of ethyl3-(3-chlorophenyl)-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate(7.40 g, 17.1 mmol) in diethyl ether (30 ml) was added to the filtrateat 0° C. The mixture was stirred for 30 min. and 1N hydrochloric acidwas added to the reaction solution to stop the reaction. Then, water(100 ml) was added and the mixture was extracted with ethyl acetate (100ml×2). The extract was washed with water and saturated brine, dried(anhydrous magnesium sulfate) and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1) to give the objective substance (6.6 g, 89%).

¹H-NMR (CDCl₃)δ: 0.95 (3H, t, J=7.2 Hz), 2.90-3.08 (3H, m), 3.10-3.16(1H, m), 3.91 (2H, q, J=7.2 Hz), 5.02 (1H, s), 5.88 (1H, tt, J=53.1, 3.0Hz), 6.92-7.08 (3H, m), 7.20-7.32 (4H, m), 7.42 (1H, s). IR νmax^(KBr)cm⁻¹: 1725, 1613, 1588, 1487, 1449. Anal. Calcd forC₂₀H₁₉O₄ClF₄: C, 55.25; H, 4.40 Found: C, 58.33; H, 4.43.

4)(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoicacid

To a solution of ethyl(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate(6.08 g, 14.0 mmol) in methanol (30 ml) was added 2N aqueous sodiumhydroxide solution (14 ml, 28 mmol), and the mixture was stirred at roomtemperature for 2 hrs. The reaction solution was acidified with 1Nhydrochloric acid and extracted with ethyl acetate (200 ml×2). Theextract was washed with water and saturated brine, dried (anhydrousmagnesium sulfate) and evaporated under reduced pressure.Recrystallization of the residue from ethyl acetate-hexane gave theobjective substance (4.6 g, 81%).

¹H-NMR (CDCl₃)δ: 2.80-3.12 (3H, m), 5.11 (1H, d, J=3.6 Hz), 5.88 (1H,tt, J=53.2, 3.0 Hz), 6.90-7.10 (3H, m), 7.18-7.32 (4H, m), 7.42 (1H, s).IR ν max^(KBr)cm⁻¹: 1713, 1613, 1588, 1489, 1451. mp 94-95° C. Anal.Calcd for C₁₈H₁₅O₄F₄: C, 53.15; H, 3.72 Found: C, 53.03; H, 3.69.

5)(4RS,5SR)-5-(3-chlorophenyl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoicacid (4.50 g, 11.1 mmol) in tetrahydrofuran (90 ml) were addeddiphenylphosphoryl azide (2.62 ml, 12.2 mmol.) and triethylamine (2.32ml, 16.6 mmol), and the mixture was heated under reflux for 4 hrs. Thereaction solution was allowed to cool and water (200 ml) was added. Themixture was extracted with ethyl acetate (100 ml×2). The extract waswashed successively with 1N hydrochloric acid, aqueous sodium hydrogencarbonate solution and saturated brine, dried (anhydrous magnesiumsulfate) and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate) and neutral aluminacolumn chromatography (ethyl acetate). Recrystallization from ethylacetate-hexane gave the objective substance (4.70 g, 100%).

¹H-NMR (CDCl₃)δ: 2.20-2.42 (2H, m), 4.20-4.34 (1H, m), 5.06 (1H, s),5.78 (1H, d, J=8.0 Hz), 5.90 (1H, tt, J=53.0, 2.6 Hz), 6.89 (1H, s),6.96 (1H, d, J=7.6 Hz), 7.06-7.18 (1H, m), 7.20-7.44 (5H, m). IR νmax^(KBr)cm⁻¹: 1767, 1613, 1588, 1489, 1435. mp 102-103° C. Anal. Calcdfor C₁₈H₁₄NO₃ClF₄: C, 53.55; H, 3.49; N, 3.47. Found: C, 53.57; H, 3.55;N, 3.38.

6)(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol

To a solution of(4RS,5SR)-5-(3-chlorophenyl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one(3.70 g, 9.16 mmol) in ethanol (30 ml) was added 8N aqueous sodiumhydroxide solution (5.7 ml, 46 mmol), and the mixture was heated underreflux for 3 hrs. The reaction solution was concentrated and dilutedwith water (100 ml). The mixture was extracted with ethyl acetate (100ml×2). The extract was washed with saturated brine, dried (anhydrousmagnesium sulfate) and evaporated under reduced pressure to give theobjective substance (3.0 g, 87%).

¹H-NMR (CDCl₃)δ: 2.38 (1H, dd, J=14.0, 10.2 Hz), 2.77 (1H, dd, J=14.0,3.0 Hz), 3.24-3.36 (1H, m), 4.67 (1H, d, J=4.8 Hz), 5.90 (1H, tt,J=53.0, 3.0 Hz), 6.94-7.18 (3H, m), 7.22-7.43 (5H, m). IR νmax^(KBr)cm⁻¹: 1613, 1586,.1487, 1449, 1431.

7)N-{(1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(448 mg, 1.24 mmol) in acetonitrile (20 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (234 mg, 1.24mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (357mg, 1.86 mmol) and 1-hydroxybenzotriazole hydrate (190 mg, 1.24 mmol),and the mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with 1Nhydrochloric acid, 1N aqueous sodium hydroxide solution and saturatedbrine, dried (anhydrous magnesium sulfate) and evaporated under reducedpressure. Recrystallization of the residue from ethyl acetate-hexanegave the objective substance (444 mg, 67%).

¹H-NMR (CDCl₃)δ: 1.92-2.04 (2H, m), 2.10-2.24 (2H, m), 2.60-2.70 (2H,m), 2.73-2.82 (1H, m), 2.90-3.00 (1H, m), 3.87 (1H, d, J=3.6 Hz),4.60-4.70 (1H, m), 5.00-5.06 (1H, m), 5.70-6.08 (2H, m), 5.80 (1H, d,J=8.4 Hz), 6.22 (1H, d, J=11.7 Hz), 6.92-7.18 (6H, m), 7.22-7.36 (4H,m), 7.47 (1H, s). IR ν max^(KBr)cm⁻¹: 1634, 1588, 1514, 1451, 1302. mp160-161° C. Anal. Calcd. for C₂₉H₂₆NO₃ClF₄: C, 63.56; H, 4.78; N, 2.56.Found: C, 63.40; H, 4.65; N, 2.42.

Example 238 tert-butyl(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-{[6-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl]methyl}ethylcarbamate

1) [6-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl]methanol

To a solution of ethyl6-(1,1,2,2-tetrafluoroethoxy)-pyridine-2-carboxylate (5.65 g, 21.2 mmol)in tetrahydrofuran (60 ml) was added Red-Al (registered trademark, 6.11g, 21.2 mmol). The reaction solution was stirred at room temperature for30 min. and acetone (2 ml) was added. Water (100 ml) was added to thereaction solution and the mixture was extracted with ethyl acetate (100ml×2). The extract was washed successively with water and saturatedbrine, dried (anhydrous magnesium sulfate) and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl-acetate=4:1) to give the objective substance (4.2 g, 88%).

¹H-NMR (CDCl₃)δ: 3.02 (1H, brs), 4.74 (2H, s), 6.17 (1H, tt, J=53.0, 3.8Hz), 6.96 (H, d, J=8.2 Hz), 7.23 (1H, d, J=8.2 Hz), 7.79 (1H, t, J=7.8Hz). IR ν max^(KBr)cm⁻¹: 1607, 1580, 1443, 1352.

2) ethyl3-(4-fluorophenyl)-3-oxo-2-{[6-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl]methyl}propanoate

To a solution of [6-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl]methanol(4.14 g, 18.39 mmol) in ethyl acetate (50 ml) were added methanesulfonylchloride (2.32 g, 20.23 mmol) and triethylamine (3.08 ml, 22.07 mmol),and the mixture was stirred at room temperature for 2 hrs. Insolublematerial was filtered off, and the filtrate was evaporated under reducedpressure to give a mesyl form. To a solution of ethyl3-(4-fluorophenyl)-3-oxopropanoate (3.87 g, 18.4 mmol) in1,2-dimethoxyethane (40 ml) was added sodium hydride (740 mg, 60% inoil, 18.4 mmol), and the mixture was stirred at room temperature for 2hrs. To the reaction solution was dropwise added a solution of the mesylform prepared earlier in 1,2-dimethoxyethane (10 ml), and the mixturewas stirred overnight at room temperature. The reaction solution wasacidified with 1N hydrochloric acid and extracted with ethyl acetate(100 ml×2). The extract was washed successively with water and saturatedbrine, dried (anhydrous magnesium sulfate) and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1-2:1) to give the objective substance (1.46 g,19%).

¹H-NMR (CDCl₃)δ: 1.15 (3H, t, J=7.0 Hz), 3.47 (2H, d, J=7.4 Hz), 4.13(2H, q, J=7.0 Hz), 5.08 (1H, t, J=7.2 Hz), 6.12 (1H, tt, J=53.0, 3.6Hz), 6.83 (1H, d, J=8.0 Hz), 7.06-7.22 (3H, m), 7.60-7.72 (1H, m),8.02-8.18 (2H, m). IR ν max^(KBr)cm⁻¹: 1738, 1688, 1601, 1578, 1508,1456, 1441.

3) ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-{[6-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl]methyl}propanoate

To a solution of zinc chloride (915 mg, 6.71 mmol) in diethyl ether (20ml) was added sodium borohydride (508 mg, 13.4 mmol), and the mixturewas-stirred at room temperature for 30 min. Insoluble material wasfiltered off, and a solution of ethyl3-(4-fluorophenyl)-3-oxo-2-{[6-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl]methyl}propanoate(1.40 g, 3.35 mmol) in diethyl ether (10 ml) was added to the filtrateat 0° C. The mixture was stirred for 30 min. and 1N hydrochloric acidwas added to the reaction solution to stop the reaction. Then, water (50ml) was added and the mixture was extracted with ethyl-acetate (50ml×2). The extract was washed with water and saturated brine, dried(anhydrous magnesium sulfate) and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1-1:1) to give the objective substance (1.28 g, 91%).

¹H-NMR (CDCl₃)δ: 1.03 (3H, t, J=7.2 Hz), 2.92-3.10 (1H, m), 3.18-3.30(2H, m), 3.43 (1H, d, J=3.3 Hz), 3.92-4.06 (2H, m), 5.04-5.10 (1H, m),6.26 (1H, tt, J=53.1, 3.9 Hz), 6.84 (1H, d, J=8.4 Hz), 6.96-7.06 (3H,m), 7.32-7.40 (2H, m), 7.64 (1H, t, J=8.1 Hz). IR ν max^(KBr)cm⁻¹: 1728,1605, 1576, 1512, 1456, 1443. Anal. Calcd for C₁₉H₁₈NO₄F₅: C, 54.42; H,4.33; N, 3.34. Found: C, 54.55; H, 4.16; N, 3.22.

4)(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-{[6-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl]methyl}propanoicacid

To a solution of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-{[6-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl]methyl}propanoate(1.28 g, 3.05 mmol) in methanol (6 ml) was added 2N aqueous sodiumhydroxide solution (3.05 ml, 6.1 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate wasadded and the mixture was extracted with ethyl acetate (50 ml×2). Theextract was washed with water and saturated brine, dried (anhydrousmagnesium sulfate) and evaporated under reduced pressure to give theobjective substance (1.20 g, 100%).

¹H-NMR (CDCl₃)δ: 2.82-3.10 (1H, m), 3.18-3.32 (2H, m), 5.24 (1H, d,J=3.9 Hz), 6.14 (1H, tt, J=53.4, 3.6 Hz), 6.84-7.08 (4H, m), 7.28-7.40(2H, m), 7.62-7.70 (1H, m). IR ν max^(KBr)cm⁻¹: 1713, 1605, 1578, 1512,1456, 1443.

5)(4RS,5SR)-5-(4-fluorophenyl)-4-{[6-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl]methyl}-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-{[6-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl]methyl}propanoicacid (1.20 g, 3.07 mmol) in tetrahydrofuran (20 ml) were addeddiphenylphosphoryl azide (730 μl, 3.37 mmol) and triethylamine (706 μl,5.06 mmol), and the mixture was heated under reflux for 4 hrs. Thereaction solution was allowed to cool and water (100 ml) was added. Themixture was extracted with ethyl acetate (50 ml×2). The extract waswashed successively with saturated aqueous sodium hydrogen carbonate,water and saturated brine, dried (anhydrous magnesium sulfate) andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=3:1-1:1) to give theobjective substance (808 mg, 68%).

¹H-NMR (CDCl₃)δ: 2.39 (1H, dd, J=15.8, 4.0 Hz), 2.58 (1H, dd, J=15.8,10.2 Hz), 4.52-4.66 (1H, m), 5.81 (1H, d, J=8.0 Hz), 6.03 (1H, tt,J=53.2, 3.0 Hz), 6.80 (1H, d, J=7.2 Hz), 6.88 (1H, d, J=8.2 Hz),7.00-7.16 (2H, m), 7.24-7.40 (2H, m), 7.63 (1H, t, J=8.0 Hz) IR νmax^(KBr)cm⁻¹: 1761, 1607, 1576, 1514, 1456, 1441.

6) tert-butyl(4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-{[6-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl]methyl}-1,3-oxazolidine-3-carboxylate

To a solution of(4RS,5SR)-5-(4-fluorophenyl)-4-{[6-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl]methyl}-1,3-oxazolidin-2-one(808 mg, 2.08 mmol) in acetonitrile (20 ml) were added di-tert-butylbicarbonate (545 mg, 2.50 mmol) and 4-N,N-dimethylaminopyridine (25.6mg, 0.21 mmol), and the mixture was stirred at room temperature for 6hrs. To the reaction solution was added water (50 ml), and the mixturewas extracted with ethyl acetate (50 ml×2). The extract was washed withsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=10:1) to give the objectivesubstance (850 g, 84%).

¹H-NMR (CDCl₃)δ: 1.53 (9H, s), 2.70 (1H, dd, J=14.8, 10.0 Hz), 3.12 (1H,dd, J=14.8, 3.4 Hz), 5.30-5.42 (1H, m), 5.70 (1H, d, J=7.4 Hz), 6.20(1H, d, J=7.2 Hz), 6.22 (1H, tdd, J=53.4, 4.4, 3.0 Hz), 6.68-6.88 (3H,m), 6.98-7.10 (2H, m), 7.30-7.40 (1H, m). IR ν max^(KBr)cm⁻¹: 1821,1725, 1607, 1578, 1514, 1456, 1443, 1370. Anal. Calcd for C₂₂H₂₁F₅N₂O₅:C, 54.10; H, 4.33; N, 5.74. Found: C, 54.06; H, 4.23; N, 5.52.

7) tert-butyl(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-{[6-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl]methyl}ethylcarbamate

To a solution of tert-butyl(4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-{[6-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl]methyl}-1,3-oxazolidine-3-carboxylate(840 mg, 1.72 mmol) in methanol (4 ml) was added a solution (4.12 ml,2.06 mmol) of 0.5N sodium hydroxide in methanol, and the mixture wasstirred at room temperature for 15 min. To the reaction solution wasadded water (50 ml), and the mixture was extracted with ethyl acetate(50 ml×2). The extract was washed with saturated brine, dried (anhydrousmagnesium sulfate) and evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane:ethylacetate=1:1) and recrystallized from ethyl acetate-hexane to give theobjective substance (390 mg, 49%).

¹H-NMR (CDCl₃)δ: 1.37 (9H, s), 2.90-3.02 (2H, m), 3.85 (1H, brs),4.16-4.30 (1H, m), 4.89 (1H, brs), 5.26 (1H, d, J=7.2 Hz), 6.19 (1H, tt,J=53.0, 3.6 Hz), 6.91 (1H, d, J=8.0 Hz), 7.00-7.14 (3H, m), 7.34-7.44(2H, m), 7.71 (1H, t, J=8.0 Hz) IR ν max^(KBr)cm⁻¹: 1694, 1605, 1578,1510, 1456, 1441. mp 109-110° C. Anal. Calcd for C₂₁H₂₃F₅N₂ _(O)₄.0.1H₂O: C, 54.34; H, 5.03; N, 6.03 Found: C, 54.12; H, 4.93; N, 5.87.

Example 239N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-{[6-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl]methyl}ethyl)-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

Trifluoroacetic acid (3 ml) was added to tert-butyl(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-{[6-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl]methyl}ethylcarbamate(300 mg, 0.65 mmol) at 0° C., and the mixture was stirred at 0° C. for10 min. To the reaction solution was added saturated aqueous sodiumhydrogen carbonate and the mixture was extracted with ethyl acetate (20ml×2). The extract was washed with saturated brine, dried (anhydrousmagnesium sulfate) and evaporated under reduced pressure. To a solutionof the residue in acetonitrile (25 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (122 mg, 0.65mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (187mg, 0.97 mmol) and 1-hydroxybenzotriazole hydrate (99 mg, 0.65 mmol),and the mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with saturatedaqueous sodium hydrogen carbonate and saturated brine, dried (anhydrousmagnesium sulfate) and evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane:ethylacetate=2:1-1:1). Recrystallization from ethyl acetate-hexane gave theobjective substance (196 mg, 57%).

¹H-NMR (CDCl₃)δ: 1.92-2.06 (2H, m), 2.14-2.24 (2H, m), 2.62-2.70 (2H,m), 3.06 (1H, dd, J=15.0, 6.9 Hz), 3.16 (1H, dd, J=15.0, 5.1 Hz), 4.34(1H, d, J=5.1 Hz), 4.70-4.82 (1H, m), 5.00 (1H, t, J=4.8 Hz), 5.88-6.26(3H, m), 6.44 (1H, d, J=7.8 Hz), 6.93 (1H, d, J=7.8 Hz), 7.00-7.12 (4H,m), 7.12-7.20 (2H, m), 7.40-7.50 (2H, m), 7.72 (1H, t, J=7.5 Hz). IR νmax^(KBr)cm⁻¹: 1645, 1605, 1576, 1508, 1456, 1441. mp 134-135° C. Anal.Calcd for C₂₈H₂₅N₂O₃F₅.0.1H₂O: C, 62.94; H., 4.75; N, 5.24. Found: C,62.84; H, 4.77; N, 5.16.

Example 240N-{(1RS,2SR)-2-[3-(benzyloxy)phenyl]-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

1) 3-benzyloxyacetophenone

To a solution of 3-hydroxyacetophenone (101 g, 744 mmol) in acetone (1L) were added potassium carbonate (154 g, 1.12 mol) and benzyl bromide(130 g, 759 mmol), and the mixture was stirred overnight at roomtemperature. The reaction solution was concentrated, diluted with water(500 ml) and extracted with ethyl acetate (500 ml×2). The extract waswashed successively with water and saturated brine, dried (anhydrousmagnesium sulfate) and evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane:ethylacetate=10:1-4:1) to give the objective substance (128 g, 76%).

¹H-NMR (CDCl₃)δ: 2.58 (3H, s), 5.11 (2H, s), 7;14-7.20 (1H, m),7.30-7.48 (6H, m), 7.54-7.60 (2H, m). IR ν max^(KBr)cm⁻¹: 1684, 1593,1582, 1497, 1483, 1439. Anal. Calcd for C₁₅H₁₄O₂: C, 79.62; H, 6.24Found: C, 79.44; H, 6.22.

2) ethyl 3-[3-(benzyloxy)phenyl]-3-oxopropanoate

To a solution of 3-benzyloxyacetophenone (90 g, 400 mmol) in diethylcarbonate (500 ml) was added ethanol (1.5 ml) and sodium hydride (60% inoil, 31.8 g, 800 mmol) was added under ice-cooling. The mixture wasstirred at room temperature for 4 hrs. To the reaction solution wasadded 6N hydrochloric acid to stop the reaction, and water (500 ml) wasadded. The mixture was extracted with ethyl acetate (500 ml×2). Theextract was washed successively with water and saturated brine, dried(anhydrous magnesium sulfate) and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=50:1-10:1) to give the objective substance (107 g, 90%).

¹H-NMR (CDCl₃)δ: 1.20-1.38 (3H, m), 3.96 (2H×6/7, s), 4.18-4.32 (2H, m),5.09 (2H×1/7, s), 5.11 (2H×6/7, s), 5.65 (1H×1/7, s), 7.02-7.60 (9H, m).IR ν max^(KBr)cm⁻¹: 1740, 1688, 1582, 1485, 1441. Anal. Calcd forC₁₅H₁₄O₂: C, 72.47; H, 6.08 Found: C, 72.77; H, 6.01.

3) ethyl3-[3-(benzyloxy)phenyl]-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate

To a solution of [3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methanol (7.91 g,35.3 mmol) in ethyl acetate (100 ml) were added methanesulfonyl chloride(3.00 ml, 38.8 mmol) and triethylamine (5.91 ml, 42.4 mmol), and themixture was stirred at room temperature for 2 hrs. Insoluble materialwas filtered off, and the filtrate was evaporated under reduced pressureto give a mesyl form. To a solution of ethyl3-[3-(benzyloxy)phenyl]-3-oxopropanoate (10 g, 33.5 mmol) in1,2-dimethoxyethane (80 ml) was added sodium hydride (1.34 g, 60% inoil, 33.5 mmol), and the mixture was stirred at room temperature for 3hrs. To the reaction solution was dropwise added a solution of the mesylform prepared earlier in 1,2-dimethoxyethane (10 ml), and the mixturewas stirred overnight at room temperature. The reaction solution wasacidified with 1N hydrochloric acid and extracted-with ethyl acetate(300 ml×2). The extract was washed successively with water and saturatedbrine, dried (anhydrous magnesium sulfate) and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1-1:1) to give the objective substance (19.0 g).

¹H-NMR (CDCl₃)δ: 1.12 (3H, t, J=7.0 Hz), 3.32 (2H, d, J=7.4 Hz), 4.09(2H, q, J=7.0 Hz), 4.56 (1H, t, J=7.4 Hz), 5.09 (2H, s), 5.88 (1H, tt,J=53.2, 3.0 Hz), 7.00-7.60 (13H, m).

4) ethyl(2RS,3RS)-3-[3-(benzyloxy)phenyl]-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate

To a solution of zinc chloride (9.14 g, 67.0 mmol) in diethyl ether (100ml) was added sodium borohydride (5.07 g, 134 mmol), and the mixture wasstirred at room temperature for 30 min. Insoluble material was filteredoff, and to the filtrate was added a solution of ethyl3-[3-(benzyloxy)phenyl]-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)-benzyl]propanoate(19.0 g, 33.5 mmol) in diethyl ether (200 ml) at 0° C. The mixture wasstirred for 30 min. and 1N hydrochloric acid was added to stop thereaction. Then, water (500 ml) was added and the mixture was extractedwith ethyl acetate (500 ml×2). The extract was washed with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:1-ethyl acetate) to give theobjective substance (10.7 g, crude).

5)(2RS,3RS)-3-[3-(benzyloxy)phenyl]-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoicacid

To a solution of ethyl(2RS,3RS)-3-[3-(benzyloxy)phenyl]-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate(10.7 g, 21.2 mmol, crude) in methanol (50 ml) was added. 2N aqueoussodium hydroxide solution (21 ml, 42 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid and extracted with ethyl acetate (50 ml×2). Theextract was washed with water and saturated brine, dried (anhydrousmagnesium sulfate) and evaporated under reduced pressure. The obtainedcrude crystals were washed with hexane to give the objective substance(7.90 g, 49% in 3 steps).

¹H-NMR (CDCl₃)δ: 2.80-3.08 (3H, m), 5.06 (2H, 5), 5.00-5.10 (1H, m),5.86 (1H, tt, J=53.2, 2.8 Hz), 6.86-7.10 (6H, m), 7.10-7.50 (7H, m). IRν max^(KBr)cm⁻¹: 1713, 1588, 1489, 1451. mp 103-104° C. Anal. Calcd forC₂₅H₂₂O₅F₄: C, 62.76; H, 4.63 Found: C, 63.01; H, 4.58.

6)(4RS,5SR)-5-[3-(benzyloxy)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-[3-(benzyloxy)phenyl]-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoicacid (7.8 g, 16.3 mmol) in tetrahydrofuran (100 ml) were addeddiphenylphosphoryl azide (3.86 ml, 17.9 mmol) and triethylamine (3.42ml, 24.5 mmol), and the mixture was heated under reflux for 4 hrs. Thereaction solution was allowed to cool and water (100 ml) was added. Themixture was extracted with ethyl acetate (100 ml×2). The extract waswashed successively with 1N hydrochloric acid, aqueous sodium hydrogencarbonate solution and saturated brine, dried (anhydrous magnesiumsulfate) and evaporated under reduced pressure. Recrystallization of theresidue from ethyl acetate-hexane gave the objective substance (6.72 g,87%).

¹H-NMR (CDCl₃)δ: 2.10-2.38 (2H, m), 4.10-4.28 (1H, m), 5.05 (1H, brs),5.10 (2H, s), 5.77 (1H, d, J=7.6 Hz), 5.90 (1H, tt, J=53.2, 2.8 Hz),6.80-7.38 (6H, m), 7.20-7.50 (7H, m). IR ν max^(KBr)cm⁻¹: 1759, 1613,1588, 1489, 1451. mp 97-99° C. Anal. Calcd for C₂₅H₂₁ NO₄F₄: C, 63.16;H, 4.45; N, 2.95. Found: C, 62.91; H, 4.30; N, 2.85.

7)(1RS,2SR)-2-amino-1-(3-(benzyloxy)phenyl)-3-(3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)-1-propanol

To a solution of(4RS,5SR)-5-[3-(benzyloxy)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one(6.5 g, 13.7 mmol) in ethanol (70 ml) was added 8N aqueous sodiumhydroxide solution (5.13 ml, 41 mmol), and the mixture was heated underreflux for 4 hrs. The reaction solution was concentrated, diluted withwater (100 ml) and extracted with ethyl acetate (100 ml×2). The extractwas washed with saturated brine, dried (anhydrous magnesium sulfate) andevaporated under reduced pressure to give the objective substance (6.26g, 100%).

¹H-NMR (CDCl₃)δ: 2.36 (1H, dd, J=14.0, 10.4 Hz), 2.82 (1H, dd, J=14.0,3.0 Hz), 3.20-3.32 (1H, m), 4.63 (1H, d, J=4.8 Hz), 5.10 (2H, s), 5.89(1H, tt, J=53.0, 3.0 Hz), 6.90-7.12 (6H, m), 7.24-7.48 (7H, m). IR νmax^(KBr)cm⁻¹: 1740, 1609, 1586, 1487, 1449. Anal. Calcd for C₂₄H₂₃NO₃F₄: C, 64.14; H, 5.16; N, 3.12. Found: C, 63.87; H, 5.26; N, 2.93.

8)N-{(1RS,2SR)-2-[3-(benzyloxy)phenyl]-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-1-(3-(benzyloxy)phenyl)-3-(3-((1,1,2,2-tetrafluoroethyl)oxy)-phenyl)-1-propanol(405 mg, 0.90 mmol) in acetonitrile (30 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (170 mg, 0.90mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (259mg, 1.35 mmol) and 1-hydroxybenzotriazole hydrate (138 mg, 0.90 mmol),and the mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with 1Nhydrochloric acid, 1N aqueous sodium hydroxide solution and saturatedbrine, dried (anhydrous magnesium sulfate) and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=2:1-1:1). Recrystallization from ethylacetate-hexane gave the objective substance (407 mg, 73%).

¹H-NMR (CDCl₃)δ: 1.92-2.02 (2H, m), 2.12-2.20 (2H, m), 2.60-2.70 (2H,m), 2.74 (1H, dd, J=14.4, 10.5 Hz), 2.96 (1H, dd, J=14.4, 3.9 Hz), 3.49(1H, d, J=3.6 Hz), 4.64-4.76 (1H, m), 5.00-5.10 (3H, m), 5.76 (1H, d,J=8.7 Hz), 5.68-6.08 (2H, m), 6.23 (1H, d, J=11.7 Hz), 6.90-7.18 (9H,m), 7.24-7.44 (7H, m). IR ν max^(KBr)cm⁻¹: 1640, 1611, 1588, 1510, 1489,1449. mp 128-129° C. Anal. Calcd for C₃₆H₃₃ NO₄F₄: C, 69.78; H, 5.37; N,2.26. Found: C, 69.62; H, 5.34; N, 2.03.

Example 241N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

1)4-{(1RS,2SR)-2-amino-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl}phenol

To a solution of(1RS,2SR)-2-amino-1-[4-(benzyloxy)phenyl]-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-propan-1-ol(2.60 g, 5.79 mmol) in ethanol (20 ml) was added 10% palladium/carbon(containing water by 50%, 260 mg), and the mixture was stirred overnightunder a hydrogen stream. The catalyst was removed from the reactionsolution using celite, and the filtrate was concentrated. The residuewas purified neutral alumina column chromatography (ethanol) to give theobjective substance (0.80 g, 39%) as an amorphous compound.

¹H-NMR (CDCl₃)δ: 2.45 (1H, dd, J=13.6, 10.0 Hz), 2.97. (1H, dd, J=13.6,2.6 Hz), 3.16-3.28 (1H, m), 4.55 (1H, d, J=5.4 Hz), 5.89 (1H, tt,J=53.2, 3.0 Hz), 6.75 (2H, d, J=8.0 Hz), 7.00-7.34 (6H, m). IR νmax^(KBr)cm⁻¹: 1613, 1588, 1514, 1489, 1449. Anal. Calcd forC₁₇H₁₇NO₃F₄.0.5H₂O: C, 55.44; H, 4.92; N, 3.80. Found: C, 55.41; H,4.83; N, 3.61.

2)N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

To a solution of4-{(1RS,2SR)-2-amino-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl}phenol(125 mg, 0.35 mmol) in acetonitrile (30 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (66 mg, 0.35mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100mg, 0.52 mmol) and 1-hydroxybenzotriazole hydrate (53 mg, 0.35 mmol),and the mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with 1Nhydrochloric acid, saturated aqueous sodium hydrogen carbonate andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:1) and recrystallized fromchloroform-hexane to give the objective substance (162 mg, 88%).

¹H-NMR (CDCl₃)δ: 1.90-2.08 (2H, m), 2.10-2.22 (2H, m), 2.58-2.70 (2H,m), 2.80 (1H, dd, J=14.4, 10.0 Hz), 3.06 (1H, dd, J=14.4, 4.0 Hz), 3.24(1H, brs), 4.64-4.82 (1H, m), 4.88 (1H, brs), 5.73 (1H, d, J=8.8 Hz),5.60-6.20 (3H, m), 6.82 (2H, d, J=8.4 Hz), 6.86-7.18 (5H, m), 7.22-7.40(3H, m). IR ν max^(KBr)cm⁻¹: 1732, 1615, 1588, 1516, 1451. mp 167-168°C. Anal. Calcd for C₂₉H₂₇NO₄F₄.0.2H₂O: C, 65.34; H, 5.18; N, 2.63.Found: C, 65.11; H, 4.99; N, 2.42.

Example 242N-{(1RS,2SR)-2-hydroxy-2-(4-methoxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

To a solution ofN-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide(400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were addedpotassium carbonate (313 mg, 2.27 mmol) and methyl iodide (2 ml), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1). Recrystallization from ethylacetate-hexane gave the objective substance (80 mg, 19%).

¹H-NMR (CDCl₃)δ: 1.90-2.06 (2H, m), 2.08-2.24 (2H, m), 2.58-2.72 (2H,m), 2.78 (1H, dd, J=14.2, 10.2 Hz), 3.02 (1H, dd, J=14.2, 4.0 Hz), 3.38(1H, brs), 3.82 (3H, s), 4.60-4.78 (1H, m), 4.94-5.00 (1H, m), 5.73 (1H,d, J=8.4 Hz), 5.60-6.24 (3H, m), 6.84-7.20 (8H, m), 7.20-7.46 (3H, m).IR ν max^(KBr)cm⁻¹: 1645, 1613, 1512, 1449. mp 151-152° C. Anal. Calcdfor C₃₀H₂₉NO₄F₄.0.1H₂O: C, 66.07; H, 5.39; N, 2.57. Found: C, 65.92; H,5.23; N, 2.51.

Example 243N-{(1RS,2SR)-2-hydroxy-2-(4-isopropoxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

To a solution ofN-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide(400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were addedpotassium carbonate (313 mg, 2.27 mmol) and 2-iodopropane (226 μl, 2.27mmol), and the mixture was stirred overnight at room temperature. Thereaction solution was diluted with water (100 ml) and extracted withethyl acetate (100 ml×2). The extract was washed successively with waterand saturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1). Recrystallization from ethylacetate-hexane gave the objective substance (287 mg, 66%).

¹H-NMR (CDCl₃)δ: 1.33 (3H, s), 1.36 (3H, s), 1.90-2.08 (2H, m),2.10-2.26 (2H, m), 2.78 (1H, dd, J=14.6, 10.2 Hz), 3.03 (1H, dd, J=14.2,4.0 Hz), 3.33 (1H, d, J=3.4 Hz), 4.48-4.62 (1H, m), 4.62-4.80 (1H, m),4.92-5.00 (1H, m), 5.72 (1H, d, J=8.4 Hz), 5.60-6.24 (3H, m), 6.84-7.20(8H, m), 7.20-7.40 (3H, m); IR ν max^(KBr)cm⁻¹: 1641, 1613, 1588, 1508,1451. mp 134-135° C. Anal. Calcd for C₃₂H₃₃NO₄F₄.0.2H₂O: C, 66.82; H,5.85; N, 2.44. Found: C, 66.72; H, 5.85; N, 2.52.

Example 244N-{(1RS,2SR)-2-(4-butoxyphenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

To a solution ofN-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide(400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were addedpotassium carbonate (313 mg, 2.27 mmol) and 1-iodobutane (417 mg, 2.27mmol), and the mixture was stirred overnight at room temperature. Thereaction solution was diluted with water (100 ml) and extracted withethyl acetate (100 ml×2). The extract was washed successively with waterand saturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. Recrystallization of the residue from ethylacetate-hexane gave the objective substance (298 mg, 67%).

¹H-NMR (CDCl₃)δ: 0.98 (3H, t, J=7.4 Hz), 1.40-1.60 (2H, m), 1.68-1.88(2H, m), 1.90-2.10 (2H, m), 2.12-2.28 (2H, m), 2.60-2.72 (2H, m), 2.77(1H, dd, J=14.6, 10.6 Hz), 3.02 (1H, dd, J=14.6, 4.0 Hz), 3.36 (1H, d,J=3.6 Hz), 3.96 (2H, t, J=6.4 Hz), 4.62-4.78 (1H, m), 4.96 (1H, t, J=4.0Hz), 5.72 (1H, d, J=8.6 Hz), 5.60-6.22 (3H, m), 6.86-7.20 (7H, m),7.22-7.40 (4H, m). IR ν max^(KBr)cm⁻¹: 1644, 1613, 1586, 1512, 1449. mp126-127° C. Anal. Calcd for C₃₃H₃₅NO₄F₄: C, 67.68; H, 6.02; N, 2.39.Found: C, 67.64; H, 6.04; N, 2.23.

Example 245N-{(1RS,2SR)-2-{4-[(4-fluorobenzyl)oxy]phenyl}-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

To a solution ofN-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide(400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were addedpotassium carbonate (313 mg, 2.27 mmol) and 4-fluorobenzyl bromide (428mg, 2.27 mmol), and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (100 ml) andextracted with ethyl acetate (100 ml×2). The extract was washedsuccessively with water and saturated brine, dried (anhydrous magnesiumsulfate) and evaporated under reduced pressure. Recrystallization of theresidue from ethyl acetate-hexane gave the objective substance (381 mg,79%).

¹H-NMR (CDCl₃)δ: 1.90-2.08 (2H, m), 2.10-2.26 (2H, m), 2.60-2.76 (2H,m), 2.77 (1H, dd, J=14.6, 10.2 Hz), 3.02 (1H, dd, J=14.6, 4.0 Hz), 3.43(1H, d, J=3.4 Hz), 4.80-4.98 (1H, m), 4.97 (1H, t, J=4.0 Hz), 5.02 (2H,s), 5.74 (1H, d, J=8.4 Hz), 5.60-6.24 (3H, m), 6.90-7.20 (10H, m),7.24-7.48 (8H, m). IR ν max^(KBr)cm⁻¹: 1644, 1611, 1586, 1512, 1449. mp144-145° C. Anal. Calcd for C₃₆H₃₂NO₄F₅: C, 67.81; H, 5.06; N, 2.20.Found: C, 67.69; H, 4.95; N, 1.98.

Example 246N-{(1RS,2SR)-2-[4-(cyclohexylmethoxy)phenyl]-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

To a solution ofN-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide(400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were addedpotassium carbonate (313 mg, 2.27 mmol) and (bromomethyl)cyclohexane(401 mg, 2.27 mmol), and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (100 ml) andextracted with ethyl acetate (100 ml×2). The extract was washedsuccessively with water and saturated brine, dried (anhydrous magnesiumsulfate) and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=1:1).Recrystallization from ethyl acetate-hexane gave the objective substance(129 mg, 27%).

¹H-NMR (CDCl₃)δ: 0.90-1.45 (6H, m), 1.66-2.10 (7H, m), 2.12-2.28 (2H,m), 2.60-2.72 (2H, m), 2.79 (1H, dd, J=14.8, 10.6 Hz), 3.03 (1H, dd,J=14.8, 4.0 Hz), 3.38 (1H, d, J=3.4 Hz), 3.77 (2H, d, J=5.8 Hz),4.64-4.80 (1H, m), 4.90-5.02 (1H, m), 5.74 (1H, d, J=8.8 Hz), 5.62-6.24(3H, m), 6.88-7.20 (7H, m), 7.20-7.42 (4H, m). IR ν max^(KBr)cm⁻¹: 1644,1613, 1586, 1512, 1451. mp 141-142° C. Anal. Calcd for C₃₆H₃₉NO₄F₄: C,69.11; H, 6.28; N, 2.24. Found: C, 69.05; H, 6.47; N, 2.14.

Example 247N-{(1RS,2SR)-2-hydroxy-2-[4-(3-phenoxypropoxy)phenyl]-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

To a solution ofN-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide(400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were addedpotassium carbonate (313 mg, 2.27 mmol) and 3-phenoxy-1-bromopropane(487 mg, 2.27 mmol), and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (100 ml) andextracted with ethyl acetate (100 ml×2). The extract was washedsuccessively with water and saturated brine, dried (anhydrous magnesiumsulfate) and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=2:1).Recrystallization from ethyl acetate-hexane gave the objective substance(245 mg, 50%).

¹H-NMR (CDCl₃)δ: 1.92-2.02 (2H, m), 2.12-2.22 (2H, m), 2.22-2.32 (2H,m), 2.62-2.70 (2H, m), 2.76 (1H, dd, J=14.4, 10.2 Hz), 3.00 (1H, dd,J=14.4, 3.9 Hz), 3.39 (1H, d, J=3.6 Hz), 4.14-4.22 (4H, m), 4.64-4.76(1H, m), 4.96-5.00 (1H, m), 5.68-6.10 (3H, m), 6.19 (1H, d, J=11.7 Hz),6.88-7.00 (6H, m), 7.00-7.16 (5H, m), 7.24-7.40 (5H, m). IR νmax^(KBr)cm⁻¹: 1644, 1613, 1601, 1588, 1512, 1499. mp 142-143° C. Anal.Calcd for C₃₈H₃₇NO₅F₄: C, 68.77; H, 5.62; N, 2.11. Found: C, 68.67;, H,5.38; N, 1.92.

Example 248 methyl4-[(4-{(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a][7]annulen-1-ylcarbonyl)amino]-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl}phenoxy)methyl]benzoate

To a solution ofN-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide(600 mg, 1.13 mmol) in N,N-dimethylformamide (20 ml) were addedpotassium carbonate (470 mg, 3.40 mmol) and methyl4-(bromomethyl)-benzoate (780 mg, 3.40 mmol), and the mixture wasstirred overnight at room temperature. The reaction solution was dilutedwith water (100 ml) and extracted with ethyl acetate (100 ml×2). Theextract was washed successively with water and saturated brine, dried(anhydrous magnesium sulfate) and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave theobjective substance (361 mg, 47%).

¹H-NMR (CDCl₃)δ: 1.90-2.08 (2H, m), 2.10-2.24 (2H, m), 2.60-2.70 (2H,m), 2.78 (1H, dd, J=14.2, 10.4 Hz), 3.02 (1H, dd, J=14.2, 4.0 Hz), 3.39(1H, s), 3.92 (3H, s), 4.60-4.80 (1H, m), 4.98 (1H, s), 5.13 (2H, s),5.72 (1H, d, J=8.8 Hz), 5.60-6.24 (3H, m), 6.90-7.18 (8H, m), 7.20-7.36(1H, m), 7.38 (2H, d, J=8.4 Hz), 7.51 (2H, d, J=8.0. Hz), 8.06 (2H, d,J=8.0 Hz). IR ν max^(KBr)cm⁻¹: 1719, 1640, 1613, 1586, 1510, 1437. mp169-170° C. Anal. Calcd for C₃₈H₃₅F₄NO₆: C, 67.35; H, 5.21; N, 2.07.Found: C, 67.19; H, 4.94; N, 1.83.

Example 249(4-{(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a][7]annulen-1-ylcarbonyl)amino]-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl}phenoxy)ethylacetate

To a solution ofN-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide(600 mg, 1.13 mmol) in N,N-dimethylformamide (20 ml) were addedpotassium carbonate (470 mg, 3.40 mmol) and ethyl bromoacetate (570 mg,3.40 mmol), and the mixture was stirred overnight at room temperature.The reaction solution was diluted with water (100 ml) and extracted withethyl acetate (100 ml×2). The extract was washed successively with waterand saturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1). Recrystallization from ethylacetate-hexane gave the objective substance (167 mg, 24%).

¹H-NMR (CDCl₃)δ: 1.30 (3H, t, J=7.2 Hz), 1.90-2.08 (2H, m), 2.12-2.24(2H, m), 2.58-2.70 (2H, m), 2.77 (1H, dd, J=14.1, 10.8 Hz), 3.00 (1H,dd, J=14.1, 3.9 Hz), 3.48 (1H, d, J=3.6 Hz), 4.28 (2H, q, J=7.2 Hz),4.63 (2H, s), 4.60-4.76 (1H, m), 4.96-5.06 (1H, m), 5.70-6.10 (3H, m),6.21 (1H, d, J=11.7 Hz), 6.88-7.20 (8H, m), 7.26-7.38 (1H, m), 7.38 (2H,d, J=8.7 Hz). IR ν max^(KBr)cm⁻¹: 1755, 1645, 1613, 1588, 1512, 1449. mp125-126° C. Anal. Calcd for C₃₃H₃₃F₄NO₆: C, 64.38; H, 5.40; N, 2.28.Found: C, 64.15; H, 5.36; N, 2.02.

Example 2504-[(4-{(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a][7]annulen-1-ylcarbonyl)amino]-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl}phenoxy)methyl]benzoicacid

To a solution of methyl4-[(4-{(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a][7]annulen-1-ylcarbonyl)amino]-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl}phenoxy)methyl]-benzoate(260 mg, 0.384 mmol) in methanol (10 ml) was added 2N aqueous sodiumhydroxide solution (0.38 ml, 0.76 mmol), and the mixture was stirred at60° C. overnight. The reaction solution was acidified with 1Nhydrochloric acid and extracted with ethyl acetate (100 ml×2). Theextract was washed with water and saturated brine, dried (anhydrousmagnesium sulfate) and evaporated under reduced pressure.Recrystallization of the residue from ethyl acetate-hexane gave theobjective substance (209 mg, 82%).

¹H-NMR (CDCl₃)δ: 1.90-2.06 (2H, m), 2.10-2.26 (2H, m), 2.60-2.80 (2H,m), 2.77 (1H, dd, J 14.6, 10.6 Hz), 3.03 (1H, dd, J=14.6, 4.4 Hz),4.62-4.80 (1H, m), 4.99 (1H, d, J=3.6 Hz), 5.15 (2H, s), 5.75 (1H, d,J=8.8 Hz), 5.58-6.24 (3H, m), 6.90-7.20 (8H, m), 7.20-7.40 (1H, m), 7.39(2H, d, J=8.4 Hz) 7.54 (2H, d, J=8.4 Hz), 8.12 (2H, d, J=8.2 Hz). IR νmax^(KBr)cm⁻¹: 1696, 1640, 1613, 1586, 1510, 1489, 1449. mp 190-191° C.Anal. Calcd for C₃₇H₃₃F₄NO₆: C, 66.96; H, 5.01; N, 2.11. Found: C,66.86; H, 4.88; N, 2.01.

Example 251(4-{(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a][7]annulen-1-ylcarbonyl)amino]-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl}phenoxy)aceticacid

To a solution of ethyl(4-{(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a][7]annulen-1-ylcarbonyl)amino]-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl}phenoxy)acetate(100 mg, 0.163 mmol) in methanol (20 ml) was added 2N aqueous sodiumhydroxide solution (0.16 ml, 0.32 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was acidified with1N hydrochloric acid and extracted with ethyl acetate (100 ml×2). Theextract was washed with water and saturated brine, dried (anhydrousmagnesium sulfate) and evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane:ethylacetate=4:1-ethyl acetate-methanol=10:1). Recrystallization from ethylacetate-hexane gave the objective substance (87 mg, 91%).

¹H-NMR (CDCl₃)δ: 1.86-2.04 (2H, m), 2.10-2.24 (2H, m), 2.58-2.70 (2H,m), 2.75 (1H, dd, J=14.6, 10.6 Hz), 2.98 (1H, dd, J=14.6, 3.6 Hz),4.50-4.96 (5H, m), 4.96 (1H, d, J=3.8 Hz), 5.58-6.20 (4H, m), 6.82-7.20(8H, m), 7.20-7.40 (3H, m). IR ν max^(KBr)cm⁻¹: 1744, 1640, 1613, 1588,1512. mp 119-120° C. Anal. Calcd for C₃₁H₂₉NO₆F₄.0.2H₂O: C, 62.99; H,5.01; N, 2.37. Found: C, 62.82; H, 5.13; N, 2.32.

Example 252N-{(1RS,2SR)-2-hydroxy-2-(3-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

1)3-{(1RS,2SR)-2-amino-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl}phenol

To a solution of(1RS,2SR)-2-amino-1-[3-(benzyloxy)-phenyl]-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(5.50 g, 12.23 mmol) in ethanol (100 ml) was added 10% palladium/carbon(containing water by 50%, 500 mg), and the mixture was stirred under ahydrogen stream overnight. The catalyst was removed from the reactionsolution using celite, and the filtrate was concentrated to give theobjective substance (4.04 g, 92%, crude). To obtain data, a portion waspurified by alumina column chromatography (ethanol) and recrystallizedfrom diisopropyl, ether-hexane.

¹H-NMR (CDCl₃)δ: 2.47 (1H, t, J=12.6 Hz), 2.99 (1H, d, J=13.5 Hz), 3.22(2H, s), 3.33 (2H, brs), 4.56 (1H, d, J=3.4 Hz), 5.88 (1H, t, J=53.1Hz), 6.70-7.40 (8H, m). IR ν max^(KBr)cm⁻¹: 1586, 1487, 1456. mp130-131° C. Anal. Calcd for C₁₇H₁₇F₄NO₃: C, 56.83; H, 4.77; N, 3.90.Found: C, 56.73; H, 4.59; N, 3.79.

2)N-{(1RS,2SR)-2-hydroxy-2-(3-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

To a solution of3-{(1RS,2SR)-2-amino-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl}phenol(2.89 g, 8.04 mmol) in acetonitrile (50 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (1.51 g, 8.04mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.31g, 12.06 mmol) and 1-hydroxybenzotriazole hydrate (1.23 g, 8.04 mmol),and the mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (200 ml) and extracted with ethylacetate (200 ml×2). The extract was washed successively with 1Nhydrochloric acid, saturated aqueous sodium hydrogen carbonate andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1-1:1) to give the objectivesubstance (2.75 g, 65%) as an amorphous compound.

¹H-NMR (CDCl₃)δ: 1.88-2.00 (2H, m), 2.08-2.18 (2H, m), 2.54-2.64 (2H,m), 2.74 (1H, dd, J=14.4, 10.5 Hz), 2.98 (1H, dd, J=14.4, 7.5 Hz), 4.07(1H, brs), 4.64-4.78 (1H, m), 4.86-4.92 (1H, m), 5.66-6.04 (4H, m),6.72-6.80 (1H, m), 6.84-7.28 (9H, m), 7.58 (1H, brs). IR νmax^(KBr)cm⁻¹: 1636, 1588, 1520, 1489, 1453. Anal. Calcd forC₂₉H₂₇NO₄F₄.0.2H₂O: C, 65.34; H, 5.18; N, 2.63. Found: C, 65.27; H,5.34; N, 2.45.

Example 253N-{(1RS,2SR)-2-hydroxy-2-(3-methoxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

To a solution ofN-{(1RS,2SR)-2-hydroxy-2-(3-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide(400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were addedpotassium carbonate (313 mg, 2.27 mmol) and methyl iodide (2 ml), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was is washed successively with waterand saturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1). Recrystallization from ethylacetate-hexane gave the objective substance (115 mg, 28%).

¹H-NMR (CDCl₃)δ: 1.90-2.06 (2H, m), 2.12-2.26 (2H, m), 2.60-2.70 (2H,m), 2.79 (1H, dd, J=14.2, 10.6 Hz), 3.00 (1H, dd, J=14.2, 4.0 Hz), 3.47(1H, d, J=3.6 Hz), 3.81 (3H, s), 4.64-4.80 (1H, m), 5.00-5.06 (1H, m),5.79 (1H, d, J=8.4 Hz), 5.60-6.26 (3H, m), 6.80-6.90 (1H, m), 6.90-7.20(7H, m), 7.20-7.38 (3H, m). IR ν max^(KBr)cm⁻¹: 1640, 1611, 1588, 1514,1489, 1453, 1439. mp 155-156° C. Anal. Calcd for C₃₀H₂₉F₄NO₄: C, 66.29;He 5.38; N, 2.58. Found: C, 66.06; H, 5.08; N, 2.36.

Example 254 tert-butyl(1RS,2RS)-2-hydroxy-2-(5-phenoxypyridin-2-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate

1) 2-methyl-5-phenoxypyridine

To a solution of 6-methylpyridin-3-ol (25.2 g, 231 mmol) inN,N-dimethylformamide (100 ml) was added potassium tert-butoxide (25.9g, 231 mmol), and the mixture was stirred at room temperature for 1 hr.The reaction solution was evaporated under reduced pressure and dilutedwith N,N-dimethylformamide (100 ml). A copper powder (3.7 g, 58 mmol)and bromobenzene (36.3 g, 231 mmol) were added, and the mixture wasstirred at 120° C. overnight. Methanol was added to the reactionsolution and insoluble material was filtered off using celite. Thefiltrate was diluted with water (500 ml) and the mixture was extractedwith ethyl acetate (500 ml×2). The extract was washed successively withwater and saturated brine, dried (anhydrous magnesium sulfate) andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1) to give theobjective substance (31 g, 72%).

¹H-NMR (CDCl₃)δ: 2.55 (3H, s), 6.94-7.04 (2H, m), 7.06-7.40 (5H, m),8.30 (1H, d, J=2.4 Hz). IR ν max^(KBr)cm⁻¹: 1603, 1590, 1574, 1483,1385. Anal. Calcd for C₁₂H₁₁NO: C, 77.81; H, 5.99; N, 7.56. Found: C,77.51; H, 5.99; N, 7.41.

2) 5-phenoxypyridine-2-carboxylic acid

To a solution of 2-methyl-5-phenoxypyridine (30 g, 162 mmol) in pyridine(90 ml) was added selenium dioxide (18.0 g, 162 mmol), and the mixturewas stirred at 110° C. overnight. The reaction solution was filteredwith celite and the filtrate was concentrated. The residue was dilutedwith chloroform (300 ml), washed successively with 0.2N aqueoushydrochloric acid solution, water and saturated brine, dried (anhydrousmagnesium sulfate), and evaporated under reduced pressure. The residuewas recrystallized from ethanol to give the objective substance (10.1 g,29%).

¹H-NMR (CDCl₃)δ: 7.04-7.18 (2H, m), 7.20-7.54 (4H, m), 8.18 (1H, d,J=8.4 Hz), 8.43 (1H, d, J=2.6 Hz), 9.59 (1H, brs). IR ν max^(KBr)cm⁻¹:1705, 1574, 1489. mp 149-150° C. Anal. Calcd for C₁₂H₉NO₃: C, 66.97; H,4.22; N, 6.51. Found: C, 66.99; H, 4.04; N, 6.42.

3) benzyl 3-oxo-3-(5-phenoxypyridin-2-yl)propanoate

To a solution of 5-phenoxypyridine-2-carboxylic acid (10 g, 46.5 mmol)in tetrahydrofuran (150 ml) was added N,N′-carbonyldiimidazole (8.29. g,51.1 mmol), and the mixture was heated under reflux for 1 hr. Aftercooling the reaction solution to room temperature, monobenzyl malonatemagnesium salt (10.5 g, 25.6 mmol) was added, and the mixture was heatedunder reflux for 2 hrs. The reaction solution was concentrated, and theresidue was purified by silica gel column chromatography (hexane:ethylacetate=2:1) to give the objective substance (11.2 g, 76%).

¹H-NMR (CDCl₃)δ: 4.19 (2H, s), 5.18 (2H, s), 7.00-7.50 (11H, m), 8.04(1H, d, J=8.8 Hz), 8.28 (1H, d, J=3.0 Hz). IR ν max^(KBr)cm⁻¹: 1740,1699, 1640, 1570, 1489, 1472.

4) benzyl3-oxo-3-(5-phenoxypyridin-2-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate

To a solution of [3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methanol (8.29 g,37.0 mmol) in ethyl acetate (100 ml) were added methanesulfonyl chloride(3.15 ml, 40.68 mmol) and triethylamine (6.19 ml, 44.4 mmol), and themixture was stirred at room temperature for 2 hrs. Insoluble materialwas filtered off, and the filtrate was evaporated under reduced pressureto give a mesyl form. To a solution of benzyl3-oxo-3-(5-phenoxypyridin-2-yl)propanoate (11.2 g, 35.1 mmol) in1,2-dimethoxyethane (80 ml) was added sodium hydride (1.41 g, 60% inoil, 35.1 mmol), and the mixture was stirred at room temperature for 1hr. To the reaction solution was dropwise added a solution of the mesylform prepared earlier in 1,2-dimethoxyethane (10 ml), and the mixturewas stirred at 70° C. overnight. The reaction solution was acidifiedwith 1N hydrochloric acid, neutralized with saturated aqueous sodiumhydrogen carbonate and extracted with ethyl acetate (300 ml×2). Theextract was washed successively with water and saturated brine, dried(anhydrous magnesium sulfate) and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1) to give the objective substance (9.32 g, 48%, crude). Thepresent compound was used for next reaction as a crude compound.

5) benzyl3-hydroxy-3-(5-phenoxypyridin-2-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate

To a solution of zinc chloride (4.57 g, 33.6 mmol) in diethyl ether (100ml) was added sodium borohydride (2.54 g, 67.1 mmol), and the mixturewas stirred at room temperature for 30 min. Insoluble material wasfiltered off, and to the filtrate was added a solution of benzyl3-oxo-3-(5-phenoxypyridin-2-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)-benzyl]propanoate(9.32 g, 16.8 mmol, crude) in diethyl ether (100 ml) at 0° C. Themixture was stirred for 30 min. and 1N hydrochloric acid was added tostop the reaction. After neutralization with saturated aqueous sodiumhydrogen carbonate, water (200 ml) was further added and the mixture wasextracted with ethyl acetate (500 ml×2). The extract was washed withwater and saturated brine, dried (anhydrous magnesium sulfate) andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=2:1-1:1) to give theobjective substance (5.07 g, 54%, crude). The present compound was usedfor the next reaction as a crude compound.

6)3-hydroxy-3-(5-phenoxypyridin-2-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoicacid

To a solution of benzyl3-hydroxy-3-(5-phenoxypyridin-2-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoicacid (5.07 g, 9.09 mmol, crude) in ethanol (500 ml) was added 10%palladium/carbon (containing water by 50%) (500 mg), and the mixture wasstirred overnight under a 1 atm hydrogen stream. The reaction solutionwas filtered with celite, and the filtrate was concentrated to give theobjective substance (4.22 g, 100%, crude). The present compound was usedfor the next reaction as a crude compound.

7)5-(5-phenoxypyridin-2-yl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one

To a solution of3-hydroxy-3-(5-phenoxypyridin-2-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoicacid (4.22 g, 9.07 mmol, crude) in tetrahydrofuran (200 ml) were addeddiphenylphosphoryl azide (2.15 ml, 9.97 mmol) and triethylamine (1.90mmol, 13.6 mmol), and the mixture was heated under reflux for 3 hrs. Thereaction solution was allowed to cool and water (100 ml) was added. Themixture was extracted with ethyl acetate (100 ml×2). The extract waswashed successively with 1N hydrochloric acid, aqueous sodium hydrogencarbonate solution and saturated brine, dried (anhydrous magnesiumsulfate) and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=2:1-1:1) togive the objective substance in a (4RS,5RS) form (1.06 g, highly polarcomponent, 25%) and a (4RS,5SR) form (1.94 g, less polar component, 46%,recrystallized from hexane-ethyl acetate). (4RS,5RS) form: ¹H-NMR(CDCl₃)δ: 2.04-2.22 (1H, m), 2.53 (1H, dd, J=14.0, 3.4 Hz), 4.38-4.50(1H, m), 5.12 (1H, s), 5.87 (1H, d, J=8.4 Hz), 5.90 (1H, tt, J=53.2, 3.0Hz), 6.90-7.48 (10H, m), 7.54 (1H, d, J=8.4 Hz), 8.39 (1H, d, J=2.6 Hz).IR ν max^(KBr)cm⁻¹: 1761, 1588, 1574, 1487. (4RS,5SR) form: ¹H-NMR(CDCl₃)δ: 2.98 (1H, dd, J=13.6, 9.2 Hz), 3.28 (1H, dd, J=13.6, 4.4 Hz),4.20-4.34 (1H, m), 5.12 (1H, brs), 5.32 (1H, d, J=5.4 Hz), 5.91 (1H, tt,J=53.2, 3.0 Hz), 7.00-7.48 (11H, m), 8.38 (1H, d, J=2.4 Hz). IR νmax^(KBr)cm⁻¹1761, 1588, 1576, 1489. mp 87-88° C. Anal. Calcd forC₂₃H₁₈F₄N₂O₄: C, 59.74; H, 3.92; N, 6.06. Found: C, 59.70; H, 3.81; N,6.03.

8) tert-butyl(4RS,5RS)-2-oxo-5-(5-phenoxypyridin-2-yl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate

To a solution of(4RS,5RS)-5-(5-phenoxypyridin-2-yl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one(1.01 g, 2.18 mmol) in acetonitrile (15 ml) were added di-tert-butyldicarbonate (571 mg, 2.62 mmol) and 4-N,N-dimethylpyridine (26.9 mg,0.22 mmol), and the mixture was stirred at room temperature for 1 hr. Tothe reaction solution was added water (50 ml) and the mixture wasextracted with ethyl acetate (50 ml×2). The extract was washedsuccessively with water and saturated brine, dried (anhydrous magnesiumsulfate) and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=10:1-1:1).Recrystallization from ethyl acetate-hexane gave the objective substance(1.07 g, 87%).

¹H-NMR (CDCl₃)δ: 1.44 (9H, s), 2.66 (1H, dd, J=14.2, 7.4 Hz), 2.83 (1H,dd, J=14.2, 5.8 Hz), 5.02 (1H, q, J=7.0 Hz), 5.70 (1H, d, J=7.0 Hz),5.88 (1H, tt, J=53.0, 3.0 Hz), 6.60 (1H, s), 6.76 (1H, d, J=7.6 Hz),6.98-7.10 (3H, m), 7.10-7.32 (3H, m), 7.34-7.50 (3H, m), 8.18 (1H, d,J=3.0 Hz). IR ν max^(KBr)cm⁻¹: 1825, 1725, 1588, 1574, 1489. mp 113-114°C. Anal. Calcd for C₂₈H₂₆N₂O₆F₄: C, 59.79; H, 4.66; N, 4.98. Found: C,59.75; H, 4.58; N, 4.90.

9) tert-butyl(1RS,2RS)-2-hydroxy-2-(5-phenoxypyridin-2-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate

To a solution of tert-butyl(4RS,5RS)-2-oxo-5-(5-phenoxypyridin-2-yl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate(1.00 g, 1.78 mmol) in methanol (12 ml) was added a solution (4.3 ml,2.13 mmol) of 0.5N sodium hydroxide in methanol, and the mixture wasstirred at room temperature for 1 hr. To the reaction solution was addedwater (50 ml), and the mixture was extracted with ethyl acetate (50ml×2). The extract was washed with saturated brine, dried (anhydrousmagnesium sulfate) and evaporated under reduced pressure. The residuewas recrystallized from ethyl acetate-hexane to give-the objectivesubstance (0.81 g, 85%).

¹H-NMR (CDCl₃)δ: 1.37 (9H, s), 2.58 (1H, dd, J=14.6, 5.4 Hz), 2.78 (1H,dd, J=14.6, 8.8 Hz), 4.10-4.30 (1H, m), 4.76 (1H, d, J=5.6 Hz),4.84-4.96 (1H, m), 5.13 (1H, d, J=9.0 Hz), 5.89 (1H, tt, J=53.0, 3.0Hz), 6.90-7.10 (5H, m), 7.12-7.30 (4H, m), 7.30-7.48 (2H, m), 8.32 (1H,s). IR ν max^(KBr)cm⁻¹: 1694, 1588, 1483. mp 129-130° C. Anal. Calcd forC₂₇H₂₈F₄N₂O₅: C, 60.44; H, 5.26; N, 5.22. Found: C, 60.21; H, 5.23; N,5.22.

Example 255N-{(1RS,2RS)-2-hydroxy-2-(5-phenoxypyridin-2-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

Trifluoroacetic acid (5 ml) was added to tert-butyl(1RS,2RS)-2-hydroxy-2-(5-phenoxypyridin-2-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate(300 mg, 0.56 mmol), and the mixture was stirred at 0° C. for 10 min.The reaction solution was neutralized with saturated aqueous sodiumhydrogen carbonate, and extracted with ethyl acetate (20 ml×2). Theextract was washed with saturated brine, dried (anhydrous magnesiumsulfate) and evaporated under reduced pressure. To the residue inacetonitrile (20 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (105 mg, 0.56mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (161mg, 0.84 mmol) and 1-hydroxybenzotriazole hydrate (86 mg, 0.56 mmol),and the mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1). Recrystallization from ethylacetate-hexane gave the objective substance (140 mg, 41%).

¹H-NMR (CDCl₃)δ: 1.92-2.12 (2H, m), 2.18-2.30 (2H, m), 2.64-2.80 (3H,m), 2.94 (1H, dd, J=14.8, 9.6 Hz), 4.78-4.92 (1H, m), 4.96 (1H, d, J=5.4Hz), 5.02-5.10 (1H, m), 5.91 (1H, tt, J=53.0, 3.0 Hz), 5.94-6.04 (1H,m), 6.30-6.44 (2H, m), 7.00-7.50 (14H, m), 8.34 (1H, d, J=2.6 Hz). IR νmax^(KBr)cm⁻¹: 1638, 1588, 1572, 1483. mp 147-148° C. Anal. Calcd forC₃₄H₃₀F₄N₂O₄: C, 67.32; H, 4.98; N, 4.62. Found: C, 67.16; H, 4.79; N,4.52.

Example 2564-fluoro-N-{(1RS,2RS)-2-hydroxy-2-(5-phenoxypyridin-2-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-1-naphthamide

To tert-butyl(1RS,2RS)-2-hydroxy-2-(5-phenoxypyridin-2-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate(300 mg, 0.56 mmol) was added trifluoroacetic acid (5 ml), and themixture was stirred at 0° C. for 10 min. The reaction solution wasneutralized with saturated aqueous sodium hydrogen carbonate andextracted with ethyl acetate (20 ml×2). The extract was washed withsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. To a solution of the residue in acetonitrile (20ml) were added 4-fluoronaphthalenecarboxylic acid (106 mg, 0.56 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (161 mg,0.84 mmol) and 1-hydroxybenzotriazole hydrate (86 mg, 0.56 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1). Recrystallization from ethylacetate-hexane gave the objective substance (133 mg, 39%).

¹H-NMR (CDCl₃)δ: 2.72 (1H, dd, J=14.4, 4.5 Hz), 2.92 (1H, dd, J=14.7,9.6 Hz), 4.88-5.00 (2H, m), 5.10-5.16 (1H, m), 5.88 (1H, tt, J=53.1, 3.0Hz), 6.55 (1H, d, J=9.0 Hz), 7.00-7.60 (15H, m), 7.98 (1H, d, J=8.1 Hz),8.10 (1H, d, J=8.1 Hz), 8.34 (1H, d, J=2.7 Hz). IR ν max^(KBr)cm⁻¹:1642, 1626, 1601, 1586, 1535, 1485. mp 146-147° C. Anal. Calcd forC₃₃H₂₅F₅N₂O₄: C, 65.13; H, 4.14; N, 4.60. Found: C, 64.99; H, 4.11; N,4.53.

Example 257 tert-butyl(1RS,2SR)-2-hydroxy-2-[4-(pyridin-2-yloxy)phenyl]-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate

1) benzyl 4-(pyridin-2-yloxy)benzoate

To a solution of benzyl 4-hydroxybenzoate (25.3 g, 111 mmol) inN,N-dimethylformamide (60 ml) was added potassium tert-butoxide (12.4 g,111 mmol), and the mixture was stirred at room temperature for 1 hr. Thereaction solution was evaporated under reduced pressure and2-bromopyridine (24.5 g, 155 mmol), a copper powder (1.76 g, 27.7 mmol)and N,N-imethylformamide (80 ml) were added. The mixture was stirred at120° C. for 8 hrs. The reaction solution was filtered with celite, andthe filtrate was evaporated under reduced pressure. To the residue wasadded water (500 ml), and the mixture was extracted with ethyl acetate(500 ml). The extract was washed successively with water and saturatedbrine, dried (anhydrous magnesium sulfate) and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=10:1). Recrystallization from ethyl acetate-hexanegave the objective substance (25.5 g, 73%).

¹H-NMR (CDCl₃)δ: 5.36 (2H, s), 6.97 (1H, d, J=8.4 Hz), 7.00-7.10 (1H,m), 7.16-7.22 (2H, m), 7.30-7.48 (5H, m), 7.68-7.78 (1H, m), 8.08-8.16(2H, m), 8.18-8.24 (1H, m). IR ν max^(KBr)cm⁻¹: 1717, 1589, 1574, 1505,1466, 1429. mp 68-69° C. Anal. Calcd for C₁₉H₁₅NO₃: C, 74.74; H, 4.95;N, 4.59. Found: C, 74.90; H, 5.14; N, 4.67.

2) 4-(pyridin-2-yloxy)benzoic acid

To a solution of benzyl 4-(pyridin-2-yloxy)benzoate (24.8 g, 81.5 mmol)in ethanol (300 ml) was added 10% palladium/carbon (containing water by50%) (2.0 g), and the mixture was stirred overnight under a hydrogenstream at 80° C. The reaction solution was filtered with celite and thefiltrate was concentrated. The residue was recrystallized from ethanolto give the objective substance (14.1 g, 80%).

¹H-NMR (CDCl₃)δ: 7.04-7.20 (2H, m), 7.20-7.52 (4H, m), 8.18 (1H, d,J=8.4 Hz), 8.43 (1H, d, J=2.6 Hz), 9.59 (1H, brs). IR ν max^(KBr)cm⁻¹:1682, 1599, 1588, 1570, 1508. mp 175-176° C. Anal. Calcd for C₁₂H₉NO₃:C, 66.97; H, 4.22; N, 6.51. Found: C, 66.78; H, 3.94; N, 6.37.

3) benzyl 3-oxo-3-[4-(pyridin-2-yloxy)phenyl]propanoate

To 4-(pyridin-2-yloxy)benzoic acid (20 g, 92.9 mmol) in tetrahydrofuran(300 ml) was added N,N′-carbonyldiimidazole (16.6 g, 102 mmol), and themixture was heated under reflux for 1 hr. After cooling the reactionsolution to room temperature, monobenzyl malonate magnesium salt (21 g,51.2 mmol) was added, and the mixture was heated under reflux for 2 hrs.The reaction solution was concentrated and the residue was purified bysilica gel column chromatography (hexane:ethyl acetate=2:1) to give theobjective substance (20.6 g, 64%).

¹H-NMR (CDCl₃)δ: 4.03 (2H, s), 5.17 (2H, s), 6.90-7.50 (7H, m),7.70-7.88 (2H, m), 7.90-8.02 (2H, m), 8.10-8.24 (2H, m). IR νmax^(KBr)cm⁻¹: 1740, 1684, 1590, 1572, 1505, 1466, 1429. Anal. Calcd forC₂₁H₁₇NO₄: C, 72.61; H, 4.93; N, 4.03. Found: C, 72.48; H, 4.88; N,4.06.

4) benzyl3-oxo-3-[4-(pyridin-2-yloxy)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate

To a solution of [3-(1,1,2,2-tetrafluoroethoxy)phenyl]methanol (6.79 g,30.3 mmol) in ethyl acetate (100 ml) were added methanesulfonyl chloride(2.58 ml, 33.3 mmol) and triethylamine (5.07 ml, 36.4 mmol), and themixture was stirred at room temperature for 2 hrs. Insoluble materialwas filtered off, and the filtrate was evaporated under reduced pressureto give a mesyl form. To a solution of benzyl3-oxo-3-[4-(pyridin-2-yloxy)phenyl]propanoate (10 g, 28.8 mmol) in1,2-dimethoxyethane (80 ml) was added sodium hydride (1.15 g, 60% inoil, 28.8 mmol), and the mixture was stirred at room temperature for 1hr. To the reaction solution was dropwise added a solution of the mesylform prepared earlier in 1,2-dimethoxyethane (10 ml), and the reactionsolution was stirred at 60° C. overnight. The reaction solution wasacidified with 1N hydrochloric acid, neutralized with saturated aqueoussodium hydrogen carbonate and extracted with ethyl acetate (300 ml×2).The extract was washed successively with water and saturated brine,dried (anhydrous magnesium sulfate) and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1) to give the objective substance (13.0 g,74%).

¹H-NMR (CDCl₃)δ: 3.35 (2H, d, J=7.5 Hz), 4.63 (1H, t, J=7.5 Hz), 5.08(2H, s), 5.88 (1H, tt, J=53.1, 3.0 Hz), 6.98-7.20 (13H, m), 7.72-7.80(1H, m), 7.96-8.02 (2H, m), 8.20-8.26 (1H, m). IR ν max^(KBr)cm⁻¹: 1738,1684, 1590, 1580.

5) benzyl(2RS,3RS)-3-hydroxy-3-[4-(pyridin-2-yloxy)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate

To a solution of zinc chloride (3.19 g, 23.4 mmol) in diethyl ether (100ml) was added sodium borohydride (1.77 g, 67.1 mmol), and the mixturewas stirred at room temperature for 30 min. Insoluble material wasfiltered off, and to the filtrate was added a solution of benzyl3-oxo-3-[4-(pyridin-2-yloxy)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate(6.5 g, 11.7 mmol) in diethyl ether (50 ml) at 0° C. The mixture wasstirred for 30 min. and 1N hydrochloric acid was added to stop thereaction. After neutralization with saturated aqueous sodium hydrogencarbonate, water (200 ml) was added and the mixture was extracted withethyl acetate (200 ml×2). The extract was washed with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1-1:1) to give the objectivesubstance (4.78 g, 73%).

¹H-NMR (CDCl₃)δ: 2.83 (1H, d, J=3.0 Hz), 2.96-3.20 (3H, m), 4.84 (2H,s), 4.98-5.04 (1H, m), 5.88 (1H, tt, J=53.2, 3.0 Hz), 6.88-7.30 (13H,m), 7.30-7.44 (2H, m), 7.62-7.76 (1H, m), 8.16-8.22 (1H, m), IR νmax^(KBr)cm⁻¹: 1728, 1593, 1507, 1468, 1429.

6)(2RS,3RS)-3-hydroxy-3-[4-(pyridin-2-yloxy)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoicacid

To a solution of benzyl(2RS,3RS)-3-hydroxy-3-[4-(pyridin-2-yloxy)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate(4.99 g, 8.95 mmol) in ethanol (500 ml) was added 10% palladium/carbon(containing water by 50%, 500 mg), and the mixture was stirred under a 1atm hydrogen stream for 2 hrs. The reaction solution was filtered withcelite and the filtrate was concentrated to give the objective substance(4.50 g, 100%, crude). The present compound was used for the nextreaction as a crude compound.

¹H-NMR (CDCl₃)δ: 2.90-3.10 (3H, m), 3.83 (1H, brs), 5.01 (1H, d, J=3.0Hz), 5.87 (1H, tt, J=53.0, 3.0 Hz), 6.86-7.16 (7H, m), 7.18-7.30 (1H,m), 7.40 (2H, d, J=8.4 Hz), 7.64-7.76 (1H, m), 8.14 (1H, d, J=3.8 Hz).IR ν max^(KBr)cm⁻¹: 1717, 1597, 1508, 1470, 1431.

7)(4RS,5SR)-5-[4-(pyridin-2-yloxy)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-hydroxy-3-[4-(pyridin-2-yloxy)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoicacid (4.49 g, 9.65 mmol, crude) in tetrahydrofuran (60 ml) were addeddiphenylphosphoryl azide (2.29 ml, 10.6 mmol) and triethylamine (2.02mmol, 14.5 mmol), and the mixture was heated under reflux for 2 hrs. Thereaction solution was allowed to cool and water (100 ml) was added. Themixture was extracted with ethyl acetate (100 ml×2). The extract waswashed successively with aqueous sodium hydrogen carbonate solution andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1-1:1). Recrystallization fromethyl acetate-hexane gave the objective substance (3.56 g, 80%).

¹H-NMR (CDCl₃)δ: 2.28-2.44 (2H, m), 4.20-4.30 (1H, m), 5.20-5.30 (1H,m), 5.81 (1H, d, J=7.5 Hz), 5.90 (1H, tt, J=53.1, 2.7 Hz), 6.84-7.00(3H, m), 7.00-7.38 (5H, m), 7.39 (2H, d, J=8.4 Hz), 7.68-7.78 (1H, m),8.16-8.24 (1H, m). IR ν max^(KBr)cm⁻¹: 1753, 1589, 1508, 1489, 1468,1431. mp 99-100° C. Anal. Calcd for C23H18N₂O₄F₄: C, 59.74; H, 3.92; N,6.06. Found: C, 59.60; H, 3.85; N, 6.11.

8) tert-butyl(4RS,5SR)-2-oxo-5-[4-(pyridin-2-yloxy)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate

To a solution of(4RS,5SR)-5-[4-(pyridin-2-yloxy)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one(3.3 g, 7.14 mmol) in acetonitrile (50 ml) were added di-tert-butyldicarbonate (1.87 g, 8.56 mmol) and 4-N,N-dimethylpyridine (87 mg, 0.71mmol), and the mixture was stirred at room temperature for 15 min. Tothe reaction solution was added water (100 ml), and the mixture wasextracted with ethyl acetate (100 ml×2). The extract was washedsuccessively with water and saturated brine, dried (anhydrous magnesiumsulfate) and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=4:1-1:1).Recrystallization from ethyl acetate-hexane gave the objective substance(3.46 g, 86%).

¹H-NMR (CDCl₃)δ: 1.50 (9H, s), 2.67 (1H, dd, J=14.2, 8.4 Hz), 2.89 (1H,dd, J=14.2, 4.8 Hz), 4.72-4.84 (1H, m), 5.71 (1H, d, J=7.0 Hz), 5.89(1H, tt, J=53.1, 3.0 Hz), 6.59 (1H, d, J=7.6 Hz), 6.66 (1H, s),6.88-7.28 (8H, m), 7.64-7.78 (1H, m), 8.16-8.22 (1H, m). IR νmax^(KBr)cm⁻¹: 1817, 1719, 1595, 1510, 1468. mp 123-124° C. Anal. Calcdfor C₂₈H₂₆N₂O₆F₄: C, 59.79; H, 4.66; N, 4.98. Found: C, 59.83; H, 4.68;N, 4.96.

9) tert-butyl(1RS,2SR)-2-hydroxy-2-[4-(pyridin-2-yloxy)phenyl]-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate

To a solution of tert-butyl(4RS,5SR)-2-oxo-5-[4-(pyridin-2-yloxy)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate(3.00 g, 5.33 mmol) in methanol (20 ml) was added a solution (12.8 ml,6.4 mmol) of 0.5N sodium hydroxide in methanol, and the mixture wasstirred at room temperature for 1 hr. To the reaction solution was addedwater (100 ml), and the mixture was extracted with ethyl acetate (100ml×2). The extract was washed with saturated brine, dried (anhydrousmagnesium sulfate) and evaporated under reduced pressure. The residuewas recrystallized from ethyl acetate-hexane to give the objectivesubstance (2.67 g, 93%).

¹H-NMR (CDCl₃)δ: 1.35 (9H, m), 2.64-2.80 (1H, m), 2.85 (1H, dd, J=15.0,4.2 Hz), 3.23 (1H, s), 4.12 (1H, s), 4.64 (1H, d, J=8.4 Hz), 4.93 (1H,s), 5.89 (1H, tt, J=53.1, 3.0 Hz), 6.92 (1H, d, J=8.4 Hz), 6.96-7.10(4H, m), 7.10-7.20 (2H, m), 7.20-7.36 (1H, m), 7.38-7.46 (2H, m),7.66-7.72 (1H, m), 8.18-8.24 (1H, m). IR ν max^(KBr)cm⁻¹: 1696, 1590,1574, 1507, 1468, 1431. mp 130-131° C. Anal. Calcd for C₂₇H₂₈F₄N₂O₅: C,60.44; H, 5.26; N, 5.22. Found: C, 60.36; H, 5.06; N, 5.23.

Example 258N-{(1RS,2SR)-2-hydroxy-2-[4-(pyridin-2-yloxy)phenyl]-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

To a solution of tert-butyl(1RS,2SR)-2-hydroxy-2-[4-(pyridin-2-yloxy)phenyl]-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate(500 mg, 0.93 mmol) was added trifluoroacetic acid (10 ml), and themixture was stirred at 0° C. for 10 min. The reaction solution wasneutralized with saturated aqueous sodium hydrogen carbonate, andextracted with ethyl acetate, (30 ml×2). The extract was washed withsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. To a solution of the residue in acetonitrile (20ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid(175 mg, 0.93 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (268 mg, 1.40 mmol) and 1-hydroxybenzotriazole hydrate(143 mg, 0.93 mmol), and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with water (150 ml), andthe mixture was extracted with ethyl acetate (100 ml×2). The extract waswashed successively with water and saturated brine, dried (anhydrousmagnesium sulfate) and evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane:ethylacetate=4:1-1:1). Recrystallization from ethyl acetate-hexane gave theobjective substance (181 mg, 32%).

¹H-NMR (CDCl₃)δ: 1.90-2.08 (2H, m), 2.10-2.24 (2H, m), 2.60-2.70 (2H,m), 2.82 (1H, dd, J=14.6, 10.6 Hz), 3.04 (1H, dd, J=14.6, 4.0 Hz), 3.71(1H, d, J=3.4 Hz), 4.62-4.80 (1H, m), 5.00-5.08 (1H, m), 5.60-6.20 (2H,m), 6.23 (1H, d, J=11.6 Hz), 6.84-7.20 (10H, m), 7.20-7.38 (1H, m), 7.48(2H, d, J=8.4 Hz), 7.64-7.76 (1H, m), 8.16-8.24 (1H, m). IR νmax^(KBr)cm⁻¹: 1644, 1590, 1507, 1468, 1429. mp 160-161° C. Anal. Calcdfor C₃₄H₃₀F₄N₂O₄: C, 67.32; H, 4.98; N, 4.62. Found: C, 67.09; H, 4.96;N, 4.56.

Example 2594-fluoro-N-{(1RS,2SR)-2-hydroxy-2-[4-(pyridin-2-yloxy)phenyl]-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-1-naphthamide

To a solution of tert-butyl(1RS,2SR)-2-hydroxy-2-[4-(pyridin-2-yloxy)phenyl]-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate(500 mg, 0.93 mmol) as added trifluoroacetic acid (10 ml), and themixture was stirred at 0° C. for 10 min. The reaction solution wasneutralized with saturated aqueous-sodium hydrogen carbonate, andextracted with ethyl acetate (30 ml×2). The extract was washed withsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. To a solution of the residue in acetonitrile (20ml) were added, 4-fluoronaphthalenecarboxylic acid (177 mg, 0.93 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (268 mg,1.40 mmol) and 1-hydroxybenzotriazole hydrate (143 mg, 0.93 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (150 ml), and the mixture was extractedwith ethyl acetate (100 ml×2). The extract was washed successively withwater and saturated brine, dried (anhydrous magnesium sulfate) andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1-1:1).Recrystallization from ethyl acetate-hexane gave the objective substance(312 mg, 55%).

¹H-NMR (CDCl₃)δ: 2.88 (1H, dd, J=14.4, 10.8 Hz), 3.11 (1H, dd, J=14.4,4.2 Hz), 3.59 (1H, s), 4.76-4.90 (1H, m), 5.08 (1H, s), 5.88 (1H, tt,J=53.1, 2.7 Hz), 6.05 (1H, d, J=7.8 Hz), 6.90-7.10 (3H, m), 7.10-7.22(6H, m), 7.22-7.38 (1H, m), 7.40-7.60 (4H, m), 7.64-7.74 (1H, m), 7.84(1H, d, J=8.4 Hz), 8.07 (1H, d, J=8.1 Hz), 8.14-8.20 (1H, m). IR νmax^(KBr)cm⁻¹: 1715, 1644, 1597, 1508, 1468, 1431. mp 176-177° C. Anal.Calcd for C₃₃H₂₅N₂O₄F₅.1.0H₂O: C, 63.26; H, 4.34; N, 4.47. Found: C,63.41; H, 4.07; N, 4.57.

Example 260 tert-butyl(1RS,2SR)-2-hydroxy-2-[4-(pyridin-3-yloxy)phenyl]-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate

1) benzyl 4-(pyridin-3-yloxy)benzoate

To a solution of benzyl 4-hydroxybenzoate (25.0 g, 110 mmol) inN,N-dimethylformamide (60 ml) was added potassium tert-butoxide (12.3 g,110 mmol), and the mixture was stirred at room temperature for 1 hr. Thereaction solution was evaporated under reduced pressure, and3-bromopyridine (25.0 g, 110 mmol), a copper powder (1.76 g, 27.2 mmol)and N,N-dimethylformamide (80 ml) were added. The mixture was stirred at120° C. for 8 hrs. The reaction solution was filtered with celite andthe filtrate was evaporated under reduced pressure. To the residue wasadded water (500 ml) and the mixture was extracted with ethyl acetate(500 ml). The extract was washed successively with water and saturatedbrine, dried (anhydrous magnesium sulfate) and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=10:1-2:1) to give the objective substance (18.0 g,54%, crude).

¹H-NMR (CDCl₃)δ: 5.36 (2H, s), 6.96-7.08 (2H, m), 7.26-7.50 (7H, m),8.04-8.12 (2H, m), 8.46 (2H, brs). IR ν max^(KBr)cm⁻¹: 1717, 1605, 1574,1505, 1474, 1424.

2) 4-(pyridin-3-yloxy)benzoic acid

To a solution of benzyl 4-(pyridin-3-yloxy)benzoate (18.0 g, 5.90 mmol)in ethanol (300 ml) was added 10% palladium/carbon (containing water by50%, 2.0 g), and the mixture was stirred under a hydrogen stream at 80°C. overnight. The reaction solution was filtered with celite and thefiltrate was concentrated. The residue was recrystallized fromethanol-hexane to give the objective substance (11.2 g, 88%).

¹H-NMR (DMSO-d₆)δ: 7.10 (2H, d, J=8.8 Hz), 7.42-7.66 (2H, m), 7.98 (2H,d, J=8.8 Hz), 8.47 (2H, s) IR ν max^(KBr)cm⁻¹: 1690, 1597, 1574. mp204-205° C. Anal. Calcd for C₁₂H₉NO₃: C, 66.97; H, 4.22; N, 6.51. Found:C, 66.88; H, 4.15; N, 6.42.

3) benzyl 3-oxo-3-[4-(pyridin-3-yloxy)phenyl]propanoate

To a solution of 4-(pyridin-3-yloxy)benzoic acid (11.2 g, 52.0 mmol) intetrahydrofuran (160 ml) was added N,N′-carbonyldiimidazole (9.28 g,57.3 mmol), and the mixture was heated under reflux for 3 hrs. Aftercooling the reaction solution to room temperature, monobenzyl malonatemagnesium salt (11.7 g, 28.6 mmol) was added, and the mixture was heatedunder reflux for 2 hrs. The reaction solution was concentrated and theresidue was purified by silica gel column chromatography (hexane:ethylacetate=1:1) to give the objective substance (14.1 g, 78%).

¹H-NMR (CDCl₃)δ: 4.02 (2H, s), 5.20 (2H, s), 6.94-7.08 (2H, m),7.30-7.48 (6H, m), 7.90-7.96 (2H, m), 8.40-8.52 (3H, m). IR νmax^(KBr)cm⁻¹: 1740, 1682, 1601, 1574, 1505, 1473, 1424.

4) benzyl3-oxo-3-[4-(pyridin-3-yloxy)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate

To a solution of [3-(1,1,2,2-tetrafluoroethoxy)phenyl]methanol (4.97 g,22.2 mmol) in ethyl acetate (100 ml) were added methanesulfonyl chloride(1.87 ml, 24.2 mmol) and triethylamine (3.65 ml, 26.2 mmol), and themixture was stirred at room temperature for 2 hrs. Insoluble materialwas filtered off, and the filtrate was evaporated under reduced pressureto give a mesyl form. To a solution of benzyl3-oxo-3-[4-(pyridin-3-yloxy)phenyl]propanoate (7 g, 20.2 mmol) in1,2-dimethoxyethane (80 ml) was added sodium hydride (806 mg, 60% inoil, 20.2 mmol), and the mixture was stirred at room temperature for 1hr. To the reaction solution was dropwise added a solution of the mesylform prepared earlier in 1,2-dimethoxyethane (10 ml), and the reactionsolution was stirred at 60° C. overnight. The reaction solution wasacidified with 1N hydrochloric acid, neutralized with saturated aqueoussodium hydrogen carbonate and extracted with ethyl acetate (300 ml×2).The extract was washed successively with water and saturated brine,dried (anhydrous magnesium sulfate) and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=2:1) to give the objective substance (6.0 g, 54%,crude).

¹H-NMR (CDCl₃)δ: 3.35 (2H, d, J=7.6 Hz), 4.60 (1H, t, J=7.6 Hz), 5.08(2H, s), 5.88 (1H, tt, J=53.0, 3.0 Hz), 6.90-7.40 (13H, m), 7.86-7.98(2H, m), 8.40-8.52 (2H, m). IR ν max^(KBr)cm⁻¹: 1740, 1684, 1601, 1574,1505, 1473, 1424.

5) benzyl(2RS,3RS)-3-hydroxy-3-[4-(pyridin-3-yloxy)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate

To a solution of zinc chloride (2.95 g, 21.6 mmol) in diethyl ether (100ml) was added sodium borohydride (1.64 g, 43.3 mmol), and the mixturewas stirred at room temperature for 30 min. Insoluble material wasfiltered off, and a solution of benzyl3-oxo-3-[4-(pyridin-3-yloxy)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate(6.0 g, 10.8 mmol, crude) in diethyl ether (50 ml) was added to thefiltrate at 0° C. The mixture was stirred for 30 min. and 1Nhydrochloric acid was added to stop the reaction. After neutralizationwith saturated aqueous sodium hydrogen carbonate, water (200 ml) wasfurther added and the mixture was extracted with ethyl acetate (200ml×2). The extract-was washed with water and saturated brine, dried(anhydrous magnesium sulfate) and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=2:1) and recrystallized from ethyl acetate-hexane to give theobjective substance (3.13 g, 73%).

¹H-NMR (CDCl₃)δ: 2.92-3.14 (4H, m), 4.86 (2H, d, J=3.3 Hz), 5.03 (1H,s), 5.88 (1H, tt, J=53.1, 3.0 Hz), 6.90-7.08 (7H, m), 7.18-7.32 (6H, m),7.36 (2H, d, J=8.4 Hz), 8.34-8.40 (2H, m). IR ν max^(KBr)cm⁻¹: 1730,1611, 1576, 1507, 1478, 1451, 1426. mp 120-122° C. Anal. Calcd forC₃₀H₂₅NO₅F₄: C, 64.86; H, 4.54; N, 2.52. Found: C, 64.91; H, 4.75; N,2.56.

6)(2RS,3RS)-3-hydroxy-3-[4-(pyridin-3-yloxy)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoicacid

To a solution of benzyl(2RS,3RS)-3-hydroxy-3-[4-(pyridin-3-yloxy)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate(3.00 g, 5.38 mmol) in ethanol (200 ml) was added 10% palladium/carbon(containing water by 50%, 300 mg), and the mixture was stirred under a 1atm hydrogen stream for 1 hr. The reaction solution was filtered withcelite and the filtrate was concentrated to give the objective substance(2.8 g, 100%, crude). The present compound was used for, the nextreaction as a crude compound.

¹H-NMR (CDCl₃)δ: 2.92-3.10 (3H, m), 5.05 (1H, m), 5.88 (1H, tt, J=53.0,3.0 Hz), 6.96-7.16 (5H, m), 7.20-7.48 (5H, m), 8.20-8.32 (2H, m). IR νmax^(KBr)cm⁻¹: 1711, 1611, 1578, 1507, 1480, 1427.

7)(4RS,5SR)-5-[4-(pyridin-3-yloxy)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-hydroxy-3-[4-(pyridin-3-yloxy)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoicacid (2.83 g, 6.08 mmol, crude) in tetrahydrofuran (100 ml) were addeddiphenylphosphoryl azide (1.44 ml, 6.69 mmol) and triethylamine (1.27mmol, 9.12 mmol), and the mixture was heated under reflux for 1 hr. Thereaction solution was allowed to cool and water (100 ml) was added. Themixture was extracted with ethyl acetate (100 ml×2). The extract waswashed successively with aqueous sodium hydrogen carbonate solution,saturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1-1:1). Recrystallization fromethyl acetate-hexane gave the objective substance (3.56 g, 73%).

¹H-NMR (CDCl₃)δ: 2.24-2.42 (2H, m), 4.22-4.32 (1H, m), 5.12-5.22 (1H,m), 5.80 (1H, d, J=7.8 Hz), 5.90 (1H, tt, J 53.1, 2.7 Hz), 6.89 (1H, s),6.96 (1H, d, J=7.8 Hz), 7.00-7.18 (3H, m), 7.26-7.40 (5H, m), 8.18-8.24(2H, m), IR ν max^(KBr)cm⁻¹: 1759, 1613, 1576, 1508, 1478, 1424. mp123-124° C. Anal. Calcd for C₂₃H₁₈N₂O₄F₄: C, 59.74; H, 3.92; N, 6.06.Found: C, 59.60; H, 3.85; N, 6.11.

8) tert-butyl(4RS,5SR)-2-oxo-5-[4-(pyridin-3-yloxy)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate

To a solution of(4RS,5SR)-5-[4-(pyridin-3-yloxy)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one(1.80 g, 3.89 mmol) in acetonitrile (40 ml) were added di-tert-butyldicarbonate (1.02 g, 4.67 mmol) and 4-N,N-dimethylpyridine (47 mg, 0.39mmol), and the mixture was stirred at room temperature for 1 hr. To thereaction solution was added water (100 ml), and the mixture wasextracted with ethyl acetate (100 ml×2). The extract was washedsuccessively with water and saturated brine, dried (anhydrous magnesiumsulfate) and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=4:1-1:1).Recrystallization from ethyl acetate-hexane gave the objective substance(1.87 g, 85%).

¹H-NMR (CDCl₃)δ: 1.51 (9H, s), 2.65 (1H, dd, J=14.2, 8.8 Hz), 2.93 (1H,dd, J=14.2, 4.4 Hz), 4.76-4.88 (1H, m), 5.69 (1H, d, J=7.0 Hz), 5.91(1H, tt, J=53.0, 3.0 Hz), 6.58 (1H, s), 6.66 (1H, d, J=7.6 Hz),6.84-7.04 (3H, m), 7.08-7.20 (3H, m), 7.26-7.36 (2H, m), 8.36-8.44 (2H,m). IR ν max^(KBr)cm⁻¹: 1819, 1721, 1613, 1578, 1508, 1476, 1424. mp146-147° C. Anal. Calcd for C₂₈H₂₆N₂O₆F₄: C, 59.79; H, 4.66; N, 4.98.Found: C, 59.83; H, 4.65; N, 4.84.

9) tert-butyl(1RS,2SR)-2-hydroxy-2-[4-(pyridin-3-yloxy)phenyl]-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate

To a solution of tert-butyl(4RS,5SR)-2-oxo-5-[4-(pyridin-3-yloxy)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate(1.70 g, 3.02 mmol) in methanol (10 ml) was added a solution (7.26 ml,3.63 mmol) of 0.5N sodium hydroxide in methanol, and the mixture wasstirred at room temperature for 1 hr. To the reaction solution was addedwater (100 ml), and the mixture was extracted with ethyl acetate (100ml×2). The extract was washed with saturated brine, dried (anhydrousmagnesium sulfate) and evaporated under reduced pressure. The residuewas recrystallized from ethyl acetate-hexane to give the objectivesubstance (1.39 g, 86%).

¹H-NMR (CDCl₃)δ: 1.35 (9H, s), 2.60-2.84 (2H, m), 3.45 (1H, s),4.02-4.16 (1H, m), 4.63 (1H, d, J=8.4 Hz), 4.93 (1H, s), 5.90 (1H, tt,J=52.8, 3.0 Hz), 6.96-7.10 (5H, m), 7.24-7.34 (3H, m), 7.41 (2H, d,J=8.4 Hz), 8.34-8.44 (2H, m). IR ν max^(KBr)cm⁻¹: 1698, 1576, 1505,1478. mp 123-124° C. Anal. Calcd for C₂₇H₂₈F₄N₂O₅: C, 60.44; H, 5.26; N,5.22. Found: C, 60.24; H, 5.45; N, 5.15.

Example 261N-{(1RS,2SR)-2-hydroxy-2-[4-(pyridin-3-yloxy)phenyl]-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

Trifluoroacetic acid (10 ml) was added to tert-butyl(1RS,2SR)-2-hydroxy-2-[4-(pyridin-3-yloxy)phenyl]-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate(500 mg, 0.93 mmol), and the mixture was stirred at 0° C. for 10 min.The reaction solution was neutralized with saturated aqueous sodiumhydrogen carbonate, and extracted with ethyl acetate (30 ml×2). Theextract was washed with saturated brine, dried (anhydrous magnesiumsulfate) and evaporated under reduced pressure. To a solution of theresidue in acetonitrile (20 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (175 mg, 0.93mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (268mg, 1.40 mmol) and 1-hydroxybenzotriazole hydrate (143 mg, 0.93 mmol),and the mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (150 ml), and the mixture was extractedwith ethyl acetate (100 ml×2). The extract was washed successively withwater and saturated brine, dried (anhydrous magnesium sulfate) andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=1:1-ethyl acetate).Recrystallization from ethyl acetate-hexane gave the objective substance(317 mg, 56%).

¹H-NMR (CDCl₃)δ: 1.90-2.08 (2H, m), 2.10-2.28 (2H, m), 2.60-2.70 (2H,m), 2.81 (1H, dd, J=14.8, 10.2 Hz), 3.02 (1H, dd, J=14.8, 4.0 Hz), 3.97(1H, s), 4.60-4.80 (1H, m), 5.00-5.08 (1H, m), 5.60-6.18 (2H, m), 6.21(1H, d, J=11.8 Hz), 6.90-7.20 (8H, m), 7.20-7.40 (3H, m), 7.40-7.52 (2H,m), 8.35 (2H, s). IR ν max^(KBr)cm⁻¹: 1642, 1613, 1576, 1505, 1478,1426. mp 133-134° C. Anal. Calcd for C₃₄H₃₀F₄N₂O₄: C, 67.12; H, 5.00; N,4.60. Found: C, 66.98; H, 4.85; N, 4.61.

Example 2624-fluoro-N-{(1RS,2SR)-2-hydroxy-2-[4-(pyridin-3-yloxy)phenyl]-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-1-naphthamide

To tert-butyl(1RS,2SR)-2-hydroxy-2-[4-(pyridin-3-yloxy)phenyl]-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate(500 mg, 0.93 mmol) was added trifluoroacetic acid (10 ml), and themixture was stirred at 0° C. for 10 min. The reaction solution wasneutralized with saturated aqueous sodium hydrogen carbonate, andextracted with ethyl acetate (30 ml×2). The extract was washed withsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. To a solution of the residue in acetonitrile (20ml) were added 4-fluoronaphthalenecarboxylic acid (177 mg, 0.93 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (268 mg,1.40 mmol) and 1-hydroxybenzotriazole hydrate (143 mg, 0.93 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (150 ml), and the mixture was extractedwith ethyl acetate (100 ml×2). The extract was washed successively withwater and saturated brine, dried (anhydrous magnesium sulfate) andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1-1:1).Recrystallization from ethyl acetate-hexane gave the objective substance(347 mg, 61%).

¹H-NMR (CDCl₃)δ: 2.89 (1H, dd, J=14.6, 10.6 Hz), 3.12 (1H, dd, J=14.6,4.0 Hz), 3.59 (1H, s), 4.70-4.90 (1H, m), 5.14 (1H, s), 5.91 (1H, tt,J=53.0, 3.0 Hz), 6.00 (1H, d, J=8.4 Hz), 6.90-7.65 (14H, m), 7.88 (1H,d, J=8.0 Hz), 8.11 (1H, d, J=8.0 Hz), 8.41 (2H, brs). IR νmax^(KBr)cm⁻¹: 1642, 1626, 1582, 1505, 1480, 1426. mp 183-184° C. Anal.Calcd for C₃₃H₂₅F₅N₂O₄: C, 65.13; H, 4.14; N, 4.60. Found: C, 65.03; H,4.01; N, 4.35.

Example 2634-fluoro-N-{(1RS,2SR)-2-(3-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-1-naphthamide

To a solution of(1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(300 mg, 0.83 mol) in acetonitrile (20 ml) were added4-fluoronaphthalenecarboxylic acid (156 mg, 0.83 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (239 mg,1.25 mmol) and 1-hydroxybenzotriazole hydrate (127 mg, 0.83 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization fromethyl acetate-hexane gave the objective substance (283 mg, 64%).

¹H-NMR (CDCl₃)δ: 2.85 (1H, dd, J=14.6, 10.6 Hz), 3.03 (1H, dd, J=14.6,4.4 Hz), 3.60 (1H, d, J=3.8 Hz), 4.68-4.86 (1H, m), 5.10-5.20 (1H, m),5.88 (1H, tt, J=53.0, 3.0 Hz), 5.99 (1H, d, J=8.4 Hz), 6.92-7.60 (12H,m), 7.84 (1H, d, J=8.0 Hz), 8.08 (1H, d, J=7.8 Hz). IR ν max^(KBr)cm⁻¹:1642, 1626, 1601, 1590, 1539. mp 175-176° C. Anal. Calcd forC₂₈H₂₁F₆NO₃.0.1H₂O: C, 62.83; H, 3.99; N, 2.62. Found: C, 62.62; H,3.79; N, 2.52.

Example 2644-fluoro-N-{(1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-1-naphthamide

To a solution of(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(300 mg, 0.79 mmol) in acetonitrile (20 ml) were added4-fluoronaphthalenecarboxylic acid (151 mg, 0.79 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (228 mg,1.19 mmol) and 1-hydroxybenzotriazole hydrate (122 mg, 0.79 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1-ethyl acetate).Recrystallization from ethyl acetate-hexane gave the objective substance(163 mg, 37%).

¹H-NMR (CDCl₃)δ: 2.84 (1H, dd, J=14.4, 10.8 Hz), 3.01 (1H, dd, J=14.4,4.2 Hz), 3.73 (1H, d, J=3.9 Hz), 4.68-4.80 (1H, m), 5.06-5.12 (1H, m),5.88 (1H, tt, J=52.8, 3.0 Hz), 6.02 (1H, d, J=8.7 Hz), 6.92-7.00 (1H,m), 7.06 (1H, s) 7.08-7.18 (3H, m), 7.24-7.40 (4H, m), 7.40-7.58 (3H,m), 7.80 (1H, d, J=8.4 Hz), 8.07 (1H, d, J=8.1 Hz). IR ν max^(KBr)cm⁻¹:1642, 1626, 1601, 1537. mp 177-178° C. Anal. Calcd for C₂₈H₂₁ClF₅NO₃: C,61.15; H, 3.85; N, 2.55. Found: C, 61.09; H, 3.70; N, 2.49.

Example 2654-fluoro-N-{(1RS,2SR)-2-(2-fluoropyridin-4-yl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-1-naphthamide

To a solution of(1RS,2SR)-2-amino-1-(2-fluoropyridin-4-yl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(194 mg, 0.54 mmol) in acetonitrile (20 ml) were added4-fluoronaphthalenecarboxylic acid (101 mg, 0.54 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 mg,0.80 mmol) and 1-hydroxybenzotriazole hydrate (82 mg, 0.54 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1-ethyl acetate).Recrystallization from ethyl acetate-hexane gave the objective substance(189 mg, 66%).

¹H-NMR (CDCl₃)δ: 2.80-3.02 (2H, m), 4.39 (1H, s), 4.62-4.80 (1H, m),5.18 (1H, s), 5.60-6.20 (1H, m), 6.27 (1H, d, J=7.4 Hz), 6.90-7.20 (6H,m), 7.20-7.40 (2H, m), 7.42-7.62 (2H, m), 7.88 (1H, d, J=8.0 Hz),8.02-8.20 (2H, d, J=6.2 Hz). IR ν max^(KBr)cm⁻¹: 1642, 1615, 1601, 1585.mp 170-171° C. Anal. Calcd for C₂₇H₂₀F₆N₂O₃.0.2H₂O: C, 60.27; H, 3.82;N, 5.21. Found: C, 60.04; H, 3.63; N, 5.20.

Example 2664-fluoro-N-{(1RS,2RS)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-1-naphthamide

To a solution of(1RS,2RS)-2-amino-1-(6-fluoropyridin-2-yl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-olhydrochloride (300 mg, 0.75 mmol) in acetonitrile (20 ml) were added4-fluoronaphthalenecarboxylic acid (141 mg, 0.75 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (216 mg,1.13 mmol), 1-hydroxybenzotriazole hydrate (115 mg, 0.75 mmol) andtriethylamine (1.03 ml, 0.75 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was diluted withwater (100 ml) and extracted with ethyl acetate (100 ml×2). The extractwas washed successively with water and saturated brine, dried (anhydrousmagnesium sulfate) and evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane:ethylacetate=2:1-ethyl acetate). Recrystallization from ethyl acetate-hexanegave the objective substance (306 mg, 76%).

¹H-NMR (CDCl₃)δ: 2.82 (1H, dd, J=14.4, 5.0 Hz), 3.02 (1H, dd, J=14.4,9.8 Hz), 4.67 (1H, d, J=5.4 Hz), 4.80-4.96 (1H, m), 5.10-5.20 (1H, m),5.88 (1H, tt, J=53.0, 3.0 Hz), 6.42 (1H, d, J=8.8 Hz), 6.89 (1H, dd,J=8.2, 2.6 Hz), 7.00-7.20 (4H, m), 7.20-7.40 (2H, m), 7.40-7.62 (3H, m),7.78-7.94 (1H, m), 7.97 (1H, d, J=8.4 Hz), 8.10 (1H, d, J=7.2 Hz). IR νmax^(KBr)cm⁻¹: 1642, 1626, 1603, 1578, 1535, 1454. mp 185-186° C. Anal.Calcd for C₂₇H₂₀F₆N₂O₃: C, 60.68; H, 3.77; N, 5.24. Found: C, 60.40; H,3.61; N, 5.14.

Example 2674-fluoro-N-{(1RS,2SR)-2-hydroxy-2-(4-phenoxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-1-naphthamide

To a solution of(1RS,2SR)-2-amino-1-(4-phenoxyphenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(300 mg, 0.69 mmol) in acetonitrile (20 ml) were added4-fluoronaphthalenecarboxylic acid (131 mg, 0.69 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg,1.03 mmol) and 1-hydroxybenzotriazole hydrate (105 mg, 0.69 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted-with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1-ethyl acetate).Recrystallization from ethyl-acetate-hexane gave the objective substance(286 mg, 68%).

¹H-NMR (CDCl₃)δ: 2.85 (1H, dd, J=14.4, 10.8 Hz), 3.10 (1H, dd, J=14.4,4.2 Hz), 3.41 (1H, d, J=3.0 Hz), 4.72-4.86 (1H, m), 5.04-5.10 (1H, m),5.88 (1H, tt, J=52.8, 3.0 Hz), 5.95 (1H, d, J=8.7 Hz), 6.94-7.04 (5H,m), 7.06-7.20 (5H, m), 7.28-7.40 (3H, m), 7.40-7.60 (4H, m), 7.81 (1H,d, J=8.4 Hz), 8.08 (1H, d, J=8.1 Hz). IR ν max^(KBr)cm⁻¹: 1644, 1626,1599, 1590, 1537, 1508, 1489. mp 155-156° C. Anal. Calcd forC₃₄H₂₆F₅NO₄: C, 67.21; H, 4.31; N, 2.31. Found: C, 67.02; H, 4.27; N,2.21.

Example 268 ethylN-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-{3-[(trifluoromethyl)thio]benzyl}ethyl)-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

1) ethyl3-(4-fluorophenyl)-3-oxo-2-{3-[(trifluoromethyl)thio]benzyl}propanoate

To a solution of 3-[(trifluoromethyl)thio]benzyl alcohol (4.82 g, 23.1mmol) in ethyl acetate (60 ml) were added methanesulfonyl chloride (2.92g, 25.5 mmol) and triethylamine (3.87 ml,27.8 mmol), and the mixture wasstirred at room temperature for 2 hrs. Insoluble material was filteredoff, and the filtrate was evaporated under reduced pressure to give amesyl form. To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropanoate(4.87 g, 23.2 mmol) in 1,2-dimethoxyethane (50 ml) was added sodiumhydride (0.93 g, 60% in oil, 23.2 mmol), and the mixture was stirred atroom temperature for 1 hr. To the reaction solution was dropwise added asolution of the mesyl form prepared earlier in 1,2-dimethoxyethane (10ml), and the reaction solution was stirred overnight at roomtemperature. The reaction solution was acidified with 1N hydrochloricacid, neutralized with saturated aqueous sodium hydrogen carbonate andextracted with ethyl acetate (300 ml×2). The extract was washedsuccessively with water and saturated brine, dried (anhydrous magnesiumsulfate) and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=4:1) andrecrystallized from ethyl acetate-hexane to give the objective substance(5.67 g, 61%).

¹H-NMR (CDCl₃)δ: 1.12 (3H, t, J=7.2 Hz), 3.26-7.42 (2H, m), 4.11 (2H, q,J=7.2 Hz), 4.56 (1H, t, J=7.5 Hz), 7.06-7.16 (2H, m), 7.26-7.38 (2H, m),7.44-7.54 (2H, m), 7.94-8.02 (2H, m). IR ν max^(KBr)cm⁻¹: 1738, 1688,1599, 1508. mp 72-73° C. Anal. Calcd for C₁₉H₁₆F₃O₃ S: C,. 57.00; H,4.03 Found: C, 56.99; H, 4.06.

2)ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-{3-[(trifluoromethyl)thio]benzyl}propanoate

To a solution of zinc chloride (3.74 g, 27.4 mmol) in diethyl ether (100ml) was added sodium borohydride (2.08 g, 54.8 mmol), and the mixturewas stirred at room temperature for 30 min. Insoluble material wasfiltered off, and to the filtrate was added a solution of ethyl3-(4-fluorophenyl)-3-oxo-2-{3-[(trifluoromethyl)thio]benzyl}propanoate(5.5 g, 13.7 mmol) in diethyl ether (50 ml) at 0° C. The mixture wasstirred for 30 min. and 1N hydrochloric acid was added to the reactionsolution to stop the reaction. After neutralization with saturatedaqueous sodium hydrogen carbonate, water (200 ml) was further added, andthe mixture was extracted with ethyl acetate (200 ml×2). The extract waswashed with water and saturated brine, dried (anhydrous magnesiumsulfate) and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=4:1) to givethe objective substance (5.40 g, 98%).

¹H-NMR (CDCl₃)δ: 0.91 (3H, t, J=7.2 Hz), 2.88-3.10 (4H, m), 3.87 (2H, q,J=7.2 Hz), 5.02 (1H, d, J=4.8 Hz), 6.98-7.12 (2H, m), 7.18-7.52 (6H, m).IR ν max^(KBr)cm⁻¹: 1725, 1605, 1510.

3)(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-{3-[(trifluoromethyl)thio]benzyl}propanoicacid

To a solution of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-{3-[(trifluoromethyl)thio]benzyl}propanoate(5.30 g, 13.17 mmol) in methanol (150 ml) was added 2N aqueous sodiumhydroxide solution (13.2 ml, 26.4 mmol), and the mixture was stirredovernight at room temperature. After the reaction solution wasconcentrated, 1N hydrochloric acid was added. The mixture was acidifiedand extracted with ethyl acetate (200 ml×2). The extract was washed withwater and saturated brine, dried (anhydrous magnesium sulfate) andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the objective substance (3.98 g, 81%).

¹H-NMR (CDCl₃)δ: 2.90-3.10 (3H, m), 5.07 (1H, s), 6.98-7.10 (2H, m),7.12-7.42 (5H, m), 7.47 (1H, d, J=7.4 Hz). IR ν max^(KBr)cm⁻¹: 1712,1607. mp 121-122° C. Anal. Calcd for C₁₇H₁₄O₃SF₄: C, 54.54; H, 3.77Found: C, 54.58; H, 3.80.

5)(4RS,5SR)-5-(4-fluorophenyl)-4-{3-[(trifluoromethyl)thio]benzyl}-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-{3-[(trifluoromethyl)thio]benzyl}propanoicacid (3.9 g, 10.42 mmol) in tetrahydrofuran (150 ml) were addeddiphenylphosphoryl azide (2.47 ml,11.5 mmol) and triethylamine (2.18 ml,15.6 mmol), and the mixture was heated under reflux for 1 hr. Thereaction solution was allowed to cool and the mixture was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1-ethyl acetate).Recrystallization from ethyl acetate-hexane gave the objective substance(3.45 g, 89%).

¹H-NMR (CDCl₃)δ: 2.31 (1H, d, J=3.0 Hz), 2.35 (1H, s), 4.20-4.34 (1H,m), 5.13 (1H, brs), 5.79 (1H, d, J=7.8 Hz), 7.04-7.20 (3H, m), 7.20-7.44(4H, m), 7.54 (1H, d, J=7.6 Hz). IR ν max^(KBr)cm⁻¹: 1755, 1609, 1595,1514. mp 132-133° C. Anal. Calcd for C₁₇H₁₃NO₂SF₄: C, 54.98; H, 3.53; N,3.77. Found: C, 55.28; H, 3.47; N, 3.98.

6)(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-{3-[(trifluoromethyl)thio]phenyl}propan-1-ol

To a solution of(4RS,5SR)-5-(4-fluorophenyl)-4-{3-[(trifluoromethyl)thio]benzyl}-1,3-oxazolidin-2-one(1.30 g, 3.50 mmol) in ethanol (3 ml) was added 8N aqueous sodiumhydroxide solution (1.31 ml,10.5 mmol), and the mixture was stirred at80° C. for 4 hrs. To the reaction solution was added water (20 ml), andthe mixture was extracted with ethyl acetate (50 ml×2). The extract waswashed with water and saturated brine, dried (anhydrous magnesiumsulfate) and evaporated under reduced pressure to give the objectivesubstance (0.8 g, 77%).

¹H-NMR (CDCl₃)δ: 1.80-2.30 (2H, m), 2.42 (1H, dd, J=13.6, 10.2 Hz), 2.83(1H, dd, J=14.0, 2.6 Hz), 3.20-3.40 (1H, m), 4.69 (1H, d, J=4.8 Hz),7.00-7.20 (2H, m), 7.20-7.56 (6H, m). IR ν max^(KBr)cm⁻¹: 1752, 1605,1508, 1476.

7)N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-{3-[(trifluoromethyl)thio]benzyl}ethyl)-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-{3-[(trifluoromethyl)thio]phenyl}propan-1-ol(450 mg, 1.51 mmol) in acetonitrile (20 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (284 mg, 1.51mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (435mg, 2.27 mmol) and 1-hydroxybenzotriazole hydrate (231 mg, 1.51 mmol),and the mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1-ethyl acetate).Recrystallization from ethyl acetate-hexane gave the objective substance(396 mg, 51%).

¹H-NMR (CDCl₃)δ: 1.90-2.08 (2H, m), 2.12-2.24 (2H, m), 2.60-2.72 (2H,m), 2.81 (1H, dd, J=14.7, 10.5 Hz), 3.00 (1H, dd, J=14.7, 4.2 Hz), 3.52(1H, d, J=3.6 Hz), 4.62-4.74 (1H, m), 5.00-5.08 (1H, m), 5.77 (1H, d,J=8.7 Hz), 5.88-5.96 (1H, m), 6.19 (1H, d, J=12.0 Hz), 6.90-7.00 (1H,m), 7.00-7.20 (4H, m), 7.30-7.60 (6H, m). IR ν max^(KBr)cm⁻¹: 1638,1512. mp 163-164° C. Anal. Calcd for C₂₈H₂₅F₄NO₂ S: C, 65.23; H, 4.89;N, 2.72; S, 6.22 Found: C, 65.02; H, 5.02; N, 2.79; S, 6.22.

Example 2694-fluoro-N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-{3-[(trifluoromethyl)thio]benzyl}ethyl)-1-naphthamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-{3-[(trifluoromethyl)thio]phenyl}propan-1-ol(450 mg, 1.51 mmol) in acetonitrile (20 ml) were added4-fluoronaphthalenecarboxylic acid (287 mg, 1.51 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (435 mg,2.27 mmol) and 1-hydroxybenzotriazole hydrate (231 mg, 1.51 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1-ethyl acetate).Recrystallization from ethyl acetate-hexane gave the objective substance(447 mg, 57%).

¹H-NMR (CDCl₃)δ: 2.85 (1H, dd, J=15.2, 10.8 Hz), 3.04 (1H, dd, J=15.0,3.9 Hz), 3.43 (1H, d, J=3.6 Hz), 4.70-4.82 (1H, m), 5.04-5.10 (1H, m),5.98 (1H, d, J=9.3 Hz), 6.92-7.02 (1H, m), 7.02-7.12 (3H, m), 7.30-7.58(8H, m), 7.77 (1H, d, J=8.7 Hz), 8.08 (1H, d, J=8.4 Hz). IR νmax^(KBr)cm⁻¹: 1642, 1626, 1601, 1537, 1512. mp 192-193° C. Anal. Calcdfor C₂₇H₂₀F₅NO₂ S: C, 62.66; H, 3.90; N, 2.71; S, 6.20 Found: C, 62.56;H, 3.86; N, 2.66; S, 6.34.

Example 270N-{(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

1) 2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxine-6-carboxylic acid

To a solution of2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxine-6-carbonitrile (5.0 g,21.44 mmol) in acetic acid (20 ml) was added conc. hydrochloric acid (20ml), and the mixture was heated under reflux overnight. The reactionsolution was concentrated, and the precipitated crystals were filteredand washed with water to give the objective substance (4.76 g, 88%).

¹H-NMR (CDCl₃)δ: 7.26 (1H, d, J=8.7 Hz), 7.90-8.00 (2H, m), 11.00-11.80(1H, br). IR ν max^(KBr)cm⁻¹: 1726, 1701, 1624, 1597, 1508. mp 103-104°C. Anal. Calcd for C₉H₄O₄F₄: C, 42.88; H, 1.60 Found: C, 43.13; H 11.60.

2) (2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methanol

To a solution of lithium aluminum hydride (1.40 g, 36.89 mmol) intetrahydrofuran (30 ml) was gradually added2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxine-6-carboxylic acid (4.65g, 18.44 mmol) at 0° C. After the reaction solution was stirred at 0° C.for 10 min., 1N aqueous sodium hydroxide solution was added. Insolublematerial was filtered off with celite and the filtrate was concentrated.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1) to give the objective substance (3.54 g,81%).

¹H-NMR (CDCl₃)δ: 1.87 (1H, t, J=6.0 Hz), 4.69 (2H, d, J=6.0 Hz),7.08-7.20 (3H, m). IR ν max^(KBr)cm⁻¹: 1611, 1510, 1441.

3) ethyl3-(4-fluorophenyl)-3-oxo-2-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]propanoate

To a solution of(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methanol (3.48 g,14.6 mmol) in ethyl acetate (100 ml) were added methanesulfonyl chloride(1.25 ml, 16.1 mmol) and triethylamine (3.05 ml, 21.9 mmol), and themixture was stirred at room temperature for 2 hrs. Insoluble materialwas filtered off, and the filtrate was evaporated under reduced pressureto give a mesyl form. To a solution of ethyl3-(4-fluorophenyl)-3-oxopropanoate (3.07 g, 14.6 mmol) in1,2-dimethoxyethane (20 ml) was added sodium hydride (0.58 g, 60% inoil, 14.6 mmol), and the mixture was stirred at room temperature for 1hr. To the reaction solution was dropwise added a solution of the mesylform prepared earlier in 1,2-dimethoxyethane (10 ml), and the mixturewas stirred overnight at room temperature. The reaction solution wasacidified with 1N hydrochloric acid, neutralized with saturated aqueoussodium hydrogen carbonate and extracted with ethyl acetate (300 ml×2).The extract was washed successively with water and saturated brine,dried (anhydrous magnesium sulfate) and evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexaneto give the objective substance (4.49 g, 71%).

¹H-NMR (CDCl₃)δ: 1.12 (3H, t, J=7.2 Hz), 3.30 (2H, d, J=7.5 Hz), 4.11(2H, q, J=7.2 Hz), 4.51 (1H, t, J=7.5 Hz), 7.03 (3H, s), 7.08-7.20 (2H,m), 7.96-8.04 (2H, m). IR ν max^(KBr)cm⁻¹: 1736, 1688, 1599, 1508. mp83-84° C. Anal. Calcd for C₂₀H₁₅O₅F₅: C, 55.82; H, 3.51 Found: C, 55.87;H, 3.42.

4) ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]propanoate

To a solution of zinc chloride (2.79 g, 20.5 mmol) in diethyl ether (100ml) was added sodium borohydride (1.55 g, 40.9 mmol), and the mixturewas stirred at room temperature for 30 min. Insoluble material wasfiltered off, and to the filtrate was added a solution of ethyl3-(4-fluorophenyl)-3-oxo-2-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]propanoate(4.4 g, 10.2 mmol) in diethyl ether (50 ml) at 0° C. The mixture wasstirred for 30 min. and 1N hydrochloric acid was added to stop thereaction. After neutralization with saturated aqueous sodium hydrogencarbonate solution, water (200 ml) was further added and the mixture wasextracted with ethyl acetate (200 ml×2). The extract was washed withwater and saturated brine, dried (anhydrous magnesium sulfate) andevaporated under reduced pressure to give the objective substance (4.40g, 100%).

¹H-NMR (CDCl₃)δ: 0.95 (3H, t, J=7.2 Hz), 2.84-3.02 (4H, m), 3.80-4.00(2H, m), 4.96-5.04 (1H, m), 6.84-6.90 (2H, m), 6.96-7.10 (3H, m),7.30-7.40 (2H, m). IR ν max^(KBr)cm⁻¹: 1725, 1607, 1510. Anal. Calcd forC₂₀H₁₇O₅F₅: C, 55.56; H, 3.96 Found: C, 55.33; H, 3.97.

5)(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]propanoicacid

To a solution of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]propanoate(4.20 g, 9.71 mmol) in methanol (20 ml) was added 2N aqueous sodiumhydroxide solution (9.7 ml, 19.4 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was concentrated,acidified with 1N hydrochloric acid and extracted with ethyl acetate(200 ml×2). The extract was washed with water and saturated brine, dried(anhydrous magnesium sulfate) and evaporated under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to give theobjective substance (3.50 g, 89%)

¹H-NMR (CDCl₃)δ: 2.84-3.10 (3H, m), 5.08 (1H, s), 6.80-6.92 (2H, m),6.92-7.12 (3H, m), 7.26-7.42 (2H, m). IR ν max^(KBr)cm⁻¹: 1752, 1676. mp90-91° C. Anal. Calcd for C₁₈H₁₃O₅F₅: C, 53.48; H, 3.24 Found: C, 53.48;H, 3.18.

6)(4RS,5SR)-5-(4-fluorophenyl)-4-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]propanoicacid (3.3 g, 8.16 mmol) in tetrahydrofuran (120 ml) were addeddiphenylphosphoryl azide (1.94 ml, 8.98. mmol) and triethylamine (1.71ml, 12.2 mmol), and the mixture was heated under reflux for 1 hr. Thereaction solution was allowed to cool and the mixture was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate). Recrystallization from ethylacetate-hexane gave the objective substance (2.74 g, 84%).

¹H-NMR (CDCl₃)δ: 2.20-2.40 (2H, m), 4.18-4.30 (1H, m), 5.28 (1H, brs),5.79 (1H, d, J=8.2 Hz), 6.77 (1H, s), 6.81 (1H, d, J=8.8 Hz), 7.00-7.20(3H, m), 7.20-7.40 (2H, m). IR ν max^(KBr)cm⁻¹: 1751, 1736, 1611, 1513.mp 191-192° C. Anal. Calcd for C₁₈H₁₂F₅NO₄: C, 53.88; H, 3.01; N, 3.49.Found: C, 54.06; H, 3.22; N, 3.60.

7)(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)propan-1-olTo a solution of(4RS,5SR)-5-(4-fluorophenyl)-4-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]-1,3-oxazolidin-2-one(1.50 g, 3.74 mmol) in ethanol (10 ml) was added 8N aqueous sodiumhydroxide solution (1.40 ml, 11.2 mmol), and the mixture was stirred at80° C. overnight.

To the reaction solution was added water (20 ml) and the mixture wasextracted with ethyl acetate (50 ml×2). The extract was washed withwater and saturated brine, dried (anhydrous magnesium sulfate) andevaporated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to give the objective substance (0.81 g, 58%).

¹H-NMR (CDCl₃)δ: 1.00-1.60 (2H, br), 2.36 (1H, dd, J=14.0, 10.2 Hz),2.80 (1H, dd, J=14.0, 2.8 Hz), 3.18-3.30 (1H, m), 4.62 (1H, d, J=5.2Hz), 6.90-7.00 (2H, m), 7.00-7.14 (3H, m), 7.30-7.42 (2H, m). IR νmax^(KBr)cm⁻¹: 1605, 1508, 1279, 1219. mp 87-88° C. Anal. Calcd forC17H₁₄F₅NO₃: C, 54.41; H, 3.76; N, 3.73. Found: C, 54.40; H, 3.66; N,3.66.

8)N-{(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)propan-1-ol(250 mg, 0.67 mmol) in acetonitrile (20 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (125 mg, 0.67mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191mg, 1.00 mmol) and 1-hydroxybenzotriazole hydrate (102 mg, 0.67 mmol),and the mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate). Recrystallization from ethylacetate-hexane gave the objective substance (257 mg, 69%).

¹H-NMR (CDCl₃)δ: 1.90-2.10 (2H, m), 2.12-2.26 (2H, m), 2.60-2.74 (2H,m), 2.79 (1H, dd, J=14.6, 10.2 Hz), 2.95 (1H, dd, J=14.6, 4.4 Hz), 3.35(1H, d, J=3.8 Hz), 4.50-4.70 (1H, m), 4.98-5.08 (1H, m), 5.78 (1H, d,J=8.8 Hz), 5.84-6.00 (1H, m), 6.19 (1H, d, J=11.6 Hz), 6.90-7.20 (8H,m), 7.38-7.50 (2H, m). IR ν max^(KBr)cm⁻¹: 1636, 1607, 1510. mp 184-185°C. Anal. Calcd for C₂₉H₂₄NO₄F₅: C, 63.85; H, 4.43; N, 2.57. Found: C,63.79; H, 4.70; N, 2.64.

Example 2714-fluoro-N-{(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]ethyl}-1-naphthamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)propan-1-ol(250 mg, 0.67 mmol) in acetonitrile (20 ml) were added4-fluoronaphthalenecarboxylic acid (127 mg, 0.67 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191 mg,1.00 mmol) and 1-hydroxybenzotriazole-hydrate (102 mg, 0.67 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate). Recrystallization from ethylacetate-hexane gave the objective substance (290 mg, 80%).

¹H-NMR (CDCl₃)δ: 2.84 (1H, dd, J=14.6, 10.6 Hz), 3.02 (1H, dd, J=14.6,4.0 Hz), 3.27 (1H, s), 4.64-4.82 (1H, m), 5.09 (1H, s), 6.04 (1H, d,J=9.0 Hz), 6.90-7.22 (7H, m), 7.36-7.66 (4H, m), 7.77 (1H, d, J=8.0 Hz),8.01 (1H, d, J=8.2 Hz). IR ν max^(KBr)cm⁻¹: 1642, 1626, 1603, 1534,1512. mp 193-194° C. Anal. Calcd for C₂₈H₁₉NO₄F₆: C, 61.43; H, 3.50; N,2.56. Found: C, 61.32; H, 3.57; N, 2.58.

Example 272N-[(1RS,2SR)-1-(4-tert-butylbenzyl)-2-(3-chlorophenyl)-2-hydroxyethyl]-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

1) ethyl 2-(4-tert-butylbenzyl)-3-(3-chlorophenyl)-3-oxopropanoate

To a solution of (4-tert-butylphenyl)methanol (14.1 g, 86.0 mmol) inethyl acetate (200 ml) were added methanesulfonyl chloride (7.47 ml,94.6 mmol) and triethylamine (18.0 ml, 129 mmol), and the mixture wasstirred at room temperature for 2 hrs. Insoluble material was filteredoff, and the filtrate was evaporated under reduced pressure to give amesyl form. To a solution of ethyl 3-(3-chlorophenyl)-3-oxopropanoate(19.5 g, 86.0 mmol) in 1,2-dimethoxyethane (100 ml) was added sodiumhydride (3.44 g, 60% in oil, 86.0 mmol), and the mixture was stirred atroom temperature for 1 hr. To the reaction solution was dropwise added asolution of the mesyl form prepared earlier in 1,2-dimethoxyethane (10ml), and the reaction solution was stirred overnight at roomtemperature. The reaction solution was acidified with 1N hydrochloricacid and extracted with ethyl acetate (300 ml×2). The extract was washedsuccessively with water and saturated brine, dried (anhydrous magnesiumsulfate) and evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=4:1) to givethe objective substance (31.1 g, 97%).

¹H-NMR (CDCl₃)δ: 1.13 (3H, t, J=7.0 Hz), 1.28 (9H, s), 3.29 (2H, d,J=7.4 Hz), 4.11 (2H, q, J=7.0 Hz), 4.54 (1H, t, J=7.4 Hz), 7.08-7.18(2H, m), 7.22-7.44 (3H, m), 7.48-7.56 (1H, m), 7.81 (1H, dt, J=7.6, 1.6Hz), 7.89 (1H, t, J=1.8 Hz). IR ν max^(KBr)cm⁻¹: 1738, 1694, 1570. Anal.Calcd for C₂₂H₂₅ClO₃ 0.1H₂O: C, 70.53; H, 6.77 Found: C, 70.38; H, 7.02.

2) ethyl(2RS,3RS)-2-(4-tert-butylbenzyl)-3-(3-chlorophenyl)-3-hydroxypropanoate

To a solution of zinc chloride (22.3 g, 163.6 mmol) in diethyl ether(500 ml) was added sodium borohydride (12.4 g, 327.2 mmol), and themixture was stirred at room temperature for 30 min. Insoluble materialwas filtered off, and to the filtrate was added a solution of ethyl2-(4-tert-butylbenzyl)-3-(3-chlorophenyl)-3-oxopropanoate (30.5 g, 81.8mmol) in diethyl ether. (200 ml) at 0° C. The mixture was stirred for 30min. and 1N hydrochloric acid was added to stop the reaction. Water (200ml) was further added, and the mixture was extracted with ethyl acetate(200 ml×2). The extract was washed with water and saturated brine; dried(anhydrous magnesium sulfate) and evaporated under reduced pressure togive the objective substance (26.8 g, 87%).

¹H-NMR (CDCl₃)δ: 0.92 (3H, t, J=7.0 Hz), 1.27 (9H, s), 2.80-3.00 (3H,m), 3.14 (1H, d, J=3.0 Hz), 3.80-4.00 (2H, m), 4.96-5.04 (1H, m), 7.01(2H, d, J=8.4 Hz), 7.18-7.30 (5H, m), 7.41 (1H, s). IR ν max^(KBr)cm⁻¹:1728, 1713, 1597, 1574. Anal. Calcd for C₂₂H₂₇ClO₃ 0.5H₂O: C, 68.83; H,7.34 Found: C, 68.71; H, 7.32.

3)(2RS,3RS)-2-(4-tert-butylbenzyl)-3-(3-chlorophenyl)-3-hydroxypropanoicacid

To a solution of ethyl(2RS,3RS)-2-(4-tert-butylbenzyl)-3-(3-chlorophenyl)-3-hydroxypropanoate(26.5 g, 70.7 mmol) in ethanol (200 ml) was added 2N aqueous sodiumhydroxide solution (70 ml, 140 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was concentrated,acidified with 1N hydrochloric acid and extracted with ethyl acetate(500 ml×2). The extract was washed with water and saturated brine, dried(anhydrous magnesium sulfate) and evaporated under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to give theobjective substance (15.0 g, 59%).

¹H-NMR (CDCl₃)δ: 1.28 (9H, s), 2.80-3.10 (3H, m), 5.08 (1H, d, J=4.0Hz), 7.00 (2H, d, J=8.4 Hz), 7.20-7.30 (5H, m), 7.41 (1H, s). IR νmax^(KBr)cm⁻¹: 1713, 1599, 1576. mp 117-118° C. Anal. Calcd forC₂₀H₂₃ClO₃: C, 69.26; H, 6.68 Found: C, 69.18; H, 6.68.

4)(4RS,5SR)-4-(4-tert-butylbenzyl)-5-(3-chlorophenyl)-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-2-(4-tert-butylbenzyl)-3-(3-chlorophenyl)-3-hydroxypropanoicacid (14.5 g, 40.6 mmol) in tetrahydrofuran (400 ml) were addeddiphenylphosphoryl azide (9.63 ml, 44.7 mmol) and triethylamine (8.50ml, 60.9 mmol), and the mixture was heated under reflux for 1 hr. Thereaction solution was cooled and evaporated under reduced pressure. Tothe residue was added water (500 ml), and mixture was extracted withethyl acetate-tetrahydrofuran. The extract was washed with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was washed with ethyl acetate togive the objective substance (9.6 g, 69%).

¹H-NMR (CDCl₃)δ: 1.29 (9H, s), 2.04-2.36 (2H, m), 4.16-4.30 (1H, m) 5.03(1H, brs), 5.76 (1H, d, J=7.6 Hz), 6.96 (2H, d, J=8.4 Hz), 7.24-7.40(6H, m). IR ν max^(KBr)cm⁻¹: 1734. mp 215-216° C. Anal. Calcd forC₂₀H₂₂Cl.NO₂: C, 69.86; H, 6.45; N, 4.07. Found: C, 69.65; H, 6.46; N,4.10.

5)(1RS,2SR)-2-amino-3-(4-tert-butylphenyl)-1-(3-chlorophenyl)propan-1-ol

To a solution of(4RS,5SR)-4-(4-tert-butylbenzyl)-5-(3-chlorophenyl)-1,3-oxazolidin-2-one(9.50 g, 27.6 mmol) in ethanol (70 ml) was added 8N aqueous sodiumhydroxide solution (17.3 ml, 138 mmol), and the mixture was stirred at80° C. overnight. To the reaction solution was added water (20 ml) andthe mixture was extracted with ethyl acetate (50 ml×2). The extract waswashed with water and saturated brine, dried (anhydrous magnesiumsulfate) and evaporated under reduced pressure to give the objectivesubstance (8.82 g, 100%).

¹H-NMR (CDCl₃)δ: 1.30 (9H, s), 2.31 (1H, dd, J=14.0, 10.6 Hz), 2.73 (1H,dd, J=14.0, 3.4 Hz), 3.22-3.34 (1H, m), 4.67 (1H, d, J=4.8 Hz), 7.05(2H, d, J=8.0 Hz), 7.24-7.36 (5H, m), 7.42 (1H, s). IR ν max^(KBr)cm⁻¹:1597, 1574, 1512, 1474.

6)N-[(1RS,2SR)-1-(4-tert-butylbenzyl)-2-(3-chlorophenyl)-2-hydroxyethyl]-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-3-(4-tert-butylphenyl)-1-(3-chlorophenyl)propan-1-ol(355 mg, 1.17 mmol) in acetonitrile (20 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (220 mg, 1.17mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (336mg, 1.76 mmol) and 1-hydroxybenzotriazole hydrate (179 mg, 1.17 mmol),and the mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization fromethyl acetate-hexane gave the objective substance (348 mg, 64%).

¹H-NMR (CDCl₃)δ: 1.30 (9H, s), 1.90-2.08 (2H, m), 2.10-2.24 (2H, m),2.60-2.78 (3H, m), 2.96 (1H, dd, J=14.4, 4.8 Hz), 4.35 (1H, d, J=4.4Hz), 4.60-4.76 (1H, m), 4.98-5.06 (1H, m), 5.67 (1H, d, J=7.8 Hz),5.88-6.02 (1H, m), 6.28 (1H, d, J=11.8 Hz), 6.88 (1H, dd, J=7.4, 1.4Hz), 6.98-7.18 (4H, m), 7.20-7.38 (8H, m), 7.47 (1H, s). IR νmax^(KBr)cm⁻¹: 1633, 1514. mp 142-143° C. Anal. Calcd for C₃₁H₃₄Cl NO₂:C, 76.29; H, 7.02; N, 2.87. Found: C, 76.19; H, 7.15; N, 2.83.

Example 273N-[(1RS,2SR)-1-(4-tert-butylbenzyl)-2-(3-chlorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide

To a solution of(1RS,2SR)-2-amino-3-(4-tert-butylphenyl)-1-(3-chlorophenyl)propan-1-ol(355 mg, 1.17 mmol) in acetonitrile (20 ml) were added4-fluoronaphthalenecarboxylic acid (223 mg, 1.17 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (336 mg,1.76 mmol) and 1-hydroxybenzotriazole hydrate (179 mg, 1.17 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively-with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization fromethyl acetate-hexane gave the objective substance (333 mg, 61%).

¹H-NMR (CDCl₃)δ: 2.74 (1H, dd, J=14.4, 11.0 Hz), 3.02 (1H, dd, J=14.4,4.4 Hz), 4.15 (1H, d, J=4.4 Hz), 4.70-4.86 (1H, m), 5.04-5.12 (1H, m),5.85 (1H, d, J=8.0 Hz), 6.90-7.20 (4H, m), 7.24-7.60 (8H, m), 7.89 (1H,d, J=7.6 Hz), 8.07 (1H, d, J=8.0 Hz) IR ν max^(KBr)cm⁻¹: 1640, 1624,1599, 1580, 1514. mp 144-145° C. Anal. Calcd for C₃₀H₂₉Cl FNO₂.0.1H₂O:C, 73.27; H, 5.98; N, 2.85. Found: C, 73.05; H, 5.74; N, 3.09.

Example 274N-[(1RS,2SR)-1-(4-tert-butylbenzyl)-2-(3-chlorophenyl)-2-hydroxyethyl]-5-chloro-1-naphthamide

To a solution of(1RS,2SR)-2-amino-3-(4-tert-butylphenyl)-1-(3-chlorophenyl)propan-1-ol(1.0 g, 3.15 mmol) in acetonitrile (40 ml) were added5-chloronaphthalenecarboxylic acid (651 mg, 3.15 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (725 mg,3.78 mmol) and 1-hydroxybenzotriazole hydrate (482 mg, 3.15 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (200 ml), and the mixture was extractedwith ethyl acetate (200 ml×2). The extract was washed successively withwater and saturated brine, dried (anhydrous magnesium sulfate) andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1-1:1).Recrystallization from ethyl acetate-hexane gave the objective substance(1.04 g, 66%).

¹H-NMR (CDCl₃)δ: 1.31 (9H, s), 2.74 (1H, dd, J=14.2, 11.0 Hz) 3.01 (1H,dd, J=14.2, 4.4 Hz), 3.98 (1H, d, J=4.4 Hz), 4.70-4.88 (1H, m),5.02-5.10 (1H, m), 5.90 (1H, d, J=8.0 Hz), 7.13 (2H, d, J=8.4 Hz),7.22-7.60 (10H, m), 7.73 (1H, d, J=8.8 Hz), 8.31 (1H, d, J=8.4 Hz). IR νmax^(KBr)cm⁻¹: 1636, 1572, 1518. mp 112-113° C. Anal. Calcd forC₃₀H₂₉Cl₂NO₂: C, 71.15; H, 5.77; N, 2.77. Found: C, 71.10; H, 5.83; N,2.56.

Example 275N-[(1RS,2SR)-1-(4-tert-butylbenzyl)-2-(3-chlorophenyl)-2-hydroxyethyl]-5-fluoro-1-naphthamide

To a solution of(1RS,2SR)-2-amino-3-(4-tert-butylphenyl)-1-(3-chlorophenyl)propan-1-ol(300 mg, 0.94 mmol) in acetonitrile (20 ml) were added5-fluoronaphthalenecarboxylic acid (180 mg, 0.94 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (217 mg,1.13 mmol) and 1-hydroxybenzotriazole hydrate (145 mg, 0.94 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1). Recrystallization from ethylacetate-hexane gave the objective substance (0.24 g, 53%).

¹H-NMR (CDCl₃)δ: 1.31 (9H, s), 2.74 (1H, dd, J=14.2, 10.6 Hz), 3.01 (1H,dd, J=14.2, 4.4 Hz), 4.02 (1H, s), 4.70-4.88 (1H, m), 5.07 (1H, t, J=4.0Hz), 5.89 (1H, d, J=7.0 Hz), 7.04-7.20 (4H, m), 7.22-7.44 (7H, m), 7.50(1H, s), 7.60 (1H, d, J=8.4 Hz), 8.12 (1H, d, J=8.4 Hz). IR νmax^(KBr)cm⁻¹: 1636, 1595, 1584, 1520, 1507. mp 102-103° C. Anal. Calcdfor C₃₀H₂₉ClFNO₂: C, 72.47; H, 6.04; N, 2.82. Found: C, 72.47; H, 6.23;N, 2.60.

Example 276N-[(1RS,2SR)-1-(4-tert-butoxybenzyl)-2-(3-chlorophenyl)-2hydroxyethyl]-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

1) ethyl 2-(4-tert-butoxylbenzyl)-3-(3-chlorophenyl)-3-oxopropanoate

To a solution of (4-tert-butoxyphenyl)methanol (5.0 g, 27.7 mmol) inethyl acetate (70 ml) were added methanesulfonyl chloride (2.36 ml, 30.5mmol) and triethylamine (5.8 ml, 41.6 mmol), and the mixture was stirredat room temperature for 2 hrs. Insoluble material was filtered off, andthe filtrate was evaporated under reduced pressure to give a mesyl form.To a solution of ethyl 3-(3-chlorophenyl)-3-oxopropanoate (6.29 g, 27.7mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (1.11 g,60% in oil, 27.7 mmol), and the mixture was stirred at room temperaturefor 1 hr. To the reaction solution was dropwise added a solution of themesyl form prepared earlier in 1,2-dimethoxyethane (10 ml), and thereaction, solution was stirred at room temperature overnight. Thereaction solution was acidified with 1N hydrochloric acid and extractedwith ethyl acetate (300 ml×2). The extract was washed successively withwater and saturated brine, dried (anhydrous magnesium sulfate) andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1) to give theobjective substance (8.26 g, 77%, crude).

2) ethyl(2RS,3RS)-2-(4-tert-butoxybenzyl)-3-(3-chlorophenyl)-3-hydroxypropanoate

To a solution of zinc chloride (5.79 g, 42.5 mmol) in diethyl ether (150ml) was added sodium borohydride (3.22 g, 85.0 mmol), and the mixturewas stirred at room temperature for 30 min. Insoluble material wasfiltered off, and to the filtrate was added a solution of ethyl2-(4-tert-butoxybenzyl)-3-(3-chlorophenyl)-3-oxopropanoate (8.26 g, 21.2mmol) in diethyl ether (100 ml) at 0° C. The mixture was stirred for 30min. and 1N hydrochloric acid was added to stop the reaction. Water (200ml) was further added and the mixture was extracted with ethyl acetate(200 ml×2). The extract was washed with water and saturated brine, dried(anhydrous magnesium sulfate) and evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=10:1-2:1) to give the objective substance (7.12 g, 86%).

¹H-NMR (CDCl₃)δ: 0.94 (3H, t, J=7.0 Hz), 1.30 (9H, s), 2.80-3.00 (3H,m), 3.12-3.22 (1H, m), 3.89 (2H, q, J=7.0 Hz), 5.01 (1H, s), 6.80-6.88(2H, m), 6.92-7.00 (2H, m), 7.20-7.30 (3H, m), 7.42 (1H, s). IR νmax^(KBr)cm⁻¹: 1726, 1609, 1597, 1574, 1507.

3)(2RS,3RS)-2-(4-tert-butoxybenzyl)-3-(3-chlorophenyl)-3-hydroxypropanoicacid

To a solution of ethyl(2RS,3RS)-2-(4-tert-butoxybenzyl)-3-(3-chlorophenyl)-3-hydroxypropanoate(7.12 g, 18.2 mmol) in methanol (60 ml) was added 2N aqueous sodiumhydroxide solution (18.2 ml, 36.4 mmol), and the mixture was stirredovernight at room temperature. The reaction solution was concentratedand acidified with 1N hydrochloric acid. The mixture was extracted withethyl acetate (200 ml×2). The extract was washed with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was recrystallized from ethylacetate-hexane to give the objective substance (4.70 g, 82%).

¹H-NMR (CDCl₃)δ: 1.29 (9H, t), 2.80-3.02 (3H, m), 5.06 (1H, d, J=4.4Hz), 6.80-6.90 (2H, m), 6.90-7.02 (2H, m), 7.20-7.30 (3H, m), 7.42 (1H,s). IR ν max^(KBr)cm⁻¹: 1713, 1705. mp 81-82° C.

4)(4RS,5SR)-4-(4-tert-butoxybenzyl)-5-(3-chlorophenyl)-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-2-(4-tert-butoxylbenzyl)-3-(3-chlorophenyl)-3-hydroxypropanoicacid (4.50 g, 14.3 mmol) in tetrahydrofuran (150 ml) were addeddiphenylphosphoryl azide (3.39 ml, 15.7 mmol) and triethylamine (3.00ml, 21.4 mmol), and the mixture was heated under reflux for 1 hr. Thereaction solution was allowed to cool and the mixture was evaporatedunder reduced pressure. To the residue was added water (200 ml), and themixture was extracted with ethyl acetate. The extract was washed withwater and saturated brine, dried (anhydrous magnesium sulfate) andevaporated under reduced pressure. The residue was recrystallized fromhexane-ethyl acetate to give the objective substance (4.01 g, 80%).

¹H-NMR (CDCl₃)δ: 1.32 (9H, s), 2.18 (1H, dd, J=13.8, 11.1 Hz), 2.28 (1H,dd, J=13.8, 3.9 Hz), 4.18-4.28 (1H, m), 4.95 (1H, s), 5.76 (1H, d, J=7.8Hz), 6.90-6.98 (2H, m), 7.24-7.30 (2H, m), 7.30-7.40 (4H, m). IR νmax^(KBr)cm⁻¹: 1734, 1507, 1476, 1435, 1391, 1364. mp 165-166° C. Anal.Calcd for C₂₀H₂₂NO₃Cl: C, 66.75; H, 6.16; N, 3.89. Found: C, 66.65; H,6.26; N, 3.69.

5)(1RS,2SR)-2-amino-3-(4-tert-butoxyphenyl)-1-(3-chlorophenyl)propan-1-ol

To a solution of(4RS,5SR)-4-(4-tert-butoxybenzyl)-5-(3-chlorophenyl)-1,3-oxazolidin-2-one(3.80 g, 10.6 mmol) in ethanol (20 ml) was added 8N aqueous sodiumhydroxide solution (3.96 ml, 31.7 mmol), and the mixture was stirred at80° C. for 6 hrs. To the reaction solution was added water (20 ml) andthe mixture was extracted with ethyl acetate (50 ml×2). The extract waswashed with water and saturated brine, dried (anhydrous magnesiumsulfate) and evaporated under reduced pressure. The residue wasrecrystallized from hexane-ethyl acetate to give the objective substance(2.67 g, 76%).

¹H-NMR (CDCl₃)δ: 1.32 (9H, s), 2.30 (1H, dd, J=13.8, 10.4 Hz), 2.70 (1H,dd, J=13.8, 3.4 Hz), 3.22-3.34 (1H, m), 4.67 (1H, d, J=4.8 Hz),6.86-6.96 (2H, m), 6.96-7.06 (2H, m), 7.20-7.34 (3H, m), 7.42 (1H, s).IR ν max^(KBr)cm⁻¹: 1574, 1507, 1476, 1366. mp 93-94° C. Anal. Calcd forC₁₉H₂₄NO₂Cl: C, 68.35; H, 7.25; N, 4.20. Found: C, 68.21; H, 7.28; N,4.18.

6)N-[(1RS,2SR)-1-(4-tert-butoxybenzyl)-2-(3-chlorophenyl)-2-hydroxyethyl]-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-3-(4-tert-butoxyphenyl)-1-(3-chlorophenyl)propan-1-ol(300 mg, 0.90 mmol) in acetonitrile (20 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (169 mg, 0.90mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (258mg, 1.35 mmol) and 1-hydroxybenzotriazole hydrate (138 mg, 0.90 mmol),and the mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization fromethyl acetate-hexane gave the objective substance (351 mg, 77%).

¹H-NMR (CDCl₃)δ: 1.32 (9H, s), 1.90-2.08 (2H, m), 2.12-2.24 (2H, m),2.60-2.76 (3H, m), 2.94 (1H, dd, J=14.6, 4.4 Hz), 4.32 (1H, d, J=4.0Hz), 4.58-4.72 (1H, m), 5.00-5.08 (1H, m), 5.73 (1H, d, J=7.6 Hz),5.92-6.08 (1H, m), 6.33 (1H, d, J=12.0 Hz), 6.88-7.20 (7H, m), 7.24-7.36(3H, m), 7.47 (1H, s). IR ν max^(KBr)cm⁻¹: 1640, 1507. mp 180-181° C.Anal. Calcd for C₃₁H₃₄NO₃Cl: C, 73.87; H, 6.80; N, 2.78. Found: C,73.62; H, 6.81; N, 2.85.

Example 277N-[(1RS,2SR)-1-(4-tert-butoxybenzyl)-2-(3-chlorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide

To a solution of(1RS,2SR)-2-amino-3-(4-tert-butoxyphenyl)-1-(3-chlorophenyl)propan-1-ol(300 mg, 0.90 mmol) in acetonitrile (20 ml) were added4-fluoronaphthalenecarboxylic acid (171 mg, 0.90 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (258 mg,1.35 mmol) and 1-hydroxybenzotriazole hydrate (138 mg, 0.90 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization fromethyl acetate-hexane gave the objective substance (278 mg, 61%).

¹H-NMR (CDCl₃)δ: 1.32 (9H, s), 2.73 (1H, dd, J=14.6, 11.0 Hz), 3.01 (1H,dd, J=14.6, 4.4 Hz), 4.13 (1H, d, J=4.0 Hz), 4.66-4.82 (1H, m), 5.10(1H, s), 5.87 (1H, d, J=8.6 Hz), 6.90-7.02 (3H, m), 7.04-7.16 (3H, m),7.26-7.38 (3H, m), 7.44-7.60 (3H, m), 7.95 (1H, d, J=7.6 Hz), 8.02-8.10(1H, m). IR ν max^(KBr)cm⁻¹: 1640, 1626, 1599, 1582, 1507. mp 161-162°C. Anal. Calcd for C₃₀H₂₉NO₃ClF: C, 71.21; H, 5.78; N, 2.77. Found: C71.10; H, 5.94; N, 2.53.

Example 278N-[(1RS,2SR)-1-(4-tert-butoxybenzyl)-2-(3-chlorophenyl)-2-hydroxyethyl]-5-chloro-1-naphthamide

To a solution of(1RS,2SR)-2-amino-3-(4-tert-butoxyphenyl)-1-(3-chlorophenyl)propan-1-ol(300 mg, 0.90 mmol) in acetonitrile (20 ml) were added5-chloronaphthalenecarboxylic acid (186 mg, 0.90 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (258 mg,1.35 mmol) and 1-hydroxybenzotriazole hydrate (138 mg, 0.90 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization fromethyl acetate-hexane gave the objective substance (136 mg, 29%).

¹H-NMR (CDCl₃)δ: 1.32 (9H, s), 2.72 (1H, dd, J=14.4, 11.0 Hz), 3.00 (1H,dd, J=14.4, 4.0 Hz), 3.96 (1H, d, J=3.6 Hz), 4.70-4.84 (1H, m), 5.09(1H, s), 5.90 (1H, d, J=8.2 Hz), 6.93 (2H, d, J=8.4 Hz), 7.10 (2H, d,J=8.4 Hz), 7.14-7.62 (8H, m), 7.78 (1H, d, J=8.4 Hz), 8.32 (1H, d, J=8.4Hz). IR ν max^(KBr)cm⁻¹: 1638, 1572, 1507. mp 132-133° C. Anal. Calcdfor C₃₀H₂₉NO₃Cl₂: C, 68.97; H, 5.59; N, 2.68. Found: C, 68.68; H, 5.69;N, 2.53.

Example 279 tert-butyl(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-{3-[(trifluoromethyl)sulfonyl]benzyl}ethylcarbamate

1) tert-butyl(4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-{3-[(trifluoromethyl)thio]benzyl}-1,3-oxazolidine-3-carboxylate

To a solution of(4RS,5RS)-5-(4-fluorophenyl)-4-{3-[(trifluoromethyl)thio]benzyl}-1,3-oxazolidin-2-one(2.06 g, 5.55 mmol) in acetonitrile (20 ml) were added di-tert-butyldicarbonate (1.45 g, 6.66 mmol) and 4-N,N-dimethylpyridine (68 mg, 0.56mmol), and the mixture was stirred at room temperature for 1 hr. To thereaction solution was added water (100 ml) and the mixture was extractedwith ethyl acetate (100 ml×2). The extract was washed successively withwater and saturated brine, dried (anhydrous magnesium sulfate) andevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=10:1-1:1).Recrystallization from ethyl acetate-hexane gave the objective substance(2.17 g, 83%).

¹H-NMR (CDCl₃)δ: 1.54 (9H, s), 2.62 (1H, dd, J=14.4, 9.0 Hz), 2.96 (1H,dd, J=14.4, 4.0 Hz), 4.76-4.88 (1H, m), 5.67 (1H, d, J=6.8 Hz), 6.73(1H, d, J=7.8 Hz), 6.82-7.00 (3H, m), 7.04-7.20 (3H, m), 7.39 (1H, d,J=7.8 Hz). IR ν max^(KBr)cm⁻¹: 1823, 1725, 1611, 1597, 1514. mp 112-113°C. Anal. Calcd for C₂₂H₂₁NO₄SF₄: C, 56.05; H, 4.49; N, 2.97. Found: C,56.08; H, 4.56; N, 2.98.

2) tert-butyl(4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-{3-[(trifluoromethyl)sulfonyl]benzyl}-1,3-oxazolidine-3-carboxylate

To a solution of tert-butyl(4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-{3-[(trifluoromethyl)thio]benzyl}-1,3-oxazolidine-3-carboxylate(1.0 g, 2.12 mmol) in acetonitrile (100 ml) was added an aqueoussolution (50 ml) of sodium periodate (1.36 g, 6.36 mmol). After thereaction solution was stirred for 10 min., ruthenium chloride (41 mg,0.21 mmol) was added, and the mixture was stirred overnight. After thereaction solution was concentrated, water (100 ml) was added and themixture was extracted with ethyl acetate (200 ml×2). The extract waswashed with water and saturated brine, dried (anhydrous magnesiumsulfate) and evaporated under reduced pressure. Recrystallization of theresidue from ethyl acetate-hexane gave the objective substance (0.93 g,87%).

¹H-NMR (CDCl₃)δ: 1.54 (9H, s), 2.76 (1H, dd, J=14.6, 9.2 Hz), 3.03 (1H,dd, J=14.6, 4.0 Hz), 4.78-4.92 (1H, m), 5.70 (1H, d, J=6.8 Hz),6.90-7.20 (5H, m), 7.30-7.44 (2H, m), 7.79 (1H, d, J=8.2 Hz). IR νmax^(KBr)cm⁻¹: 1817, 1725, 1611, 1514. mp 158-159° C. Anal. Calcd forC₂₂H₂₁NO₆SF₄: C, 52.48; H, 4.20; N, 2.78; F, 15.09; S, 6.37 Found: C,52.51; H, 4.00; N, 2.55; F, 15.06; S, 6.40.

3) tert-butyl(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-{3-[(trifluoromethyl)sulfonyl]benzyl}ethylcarbamate

To a solution of tert-butyl(4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-{3-[(trifluoromethyl)sulfonyl]benzyl}-1,3-oxazolidine-3-carboxylate(0.90 g, 1.79 mmol) in methanol (10 ml) was added a solution of 0.5Nsodium hydroxide in methanol (10.8 ml, 5.40 mmol), and the mixture wasstirred at room temperature for 30 min. To the reaction solution wasadded water (50 ml), and the mixture was extracted with ethyl acetate(100 ml×2). The extract was washed with saturated brine, dried(anhydrous magnesium sulfate) and evaporated under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to give theobjective substance (0.72 g, 84%).

¹H-NMR (CDCl₃)δ: 1.31 (9H, s), 2.74-3.00 (3H, m), 3.96-4.16 (1H, m),4.69 (1H, d, J=8.4 Hz), 4.95 (1H, s), 7.02-7.14 (2H, m), 7.32-7.44 (2H,m), 7.50-7.64 (2H, m), 7.77 (1H, s), 7.87 (1H, d, J=6.6 Hz). IR νmax^(KBr)cm⁻¹: 1694, 1510, 1368. mp 152-153° C. Anal. Calcd forC₂₁H₂₃NO₅SF₄: C, 52.83; H, 4.86; N, 2.93. Found: C, 52.67; H, 4.74; N,2.97.

Example 280N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-{3-[(trifluoromethyl)sulfonyl]benzyl}ethyl)-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

1)(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-{3-[(trifluoromethyl)sulfonyl]phenyl}propan-1-ol

To a solution of tert-butyl(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-{3-[(trifluoromethyl)sulfonyl]benzyl}-ethylcarbamate(620 mg, 1.30 mmol) was added trifluoroacetic acid (5 ml), and mixturewas stirred at 0° C. for 10 min. After the reaction solution wasconcentrated, saturated aqueous sodium hydrogen carbonate was added andthe mixture was extracted with ethyl acetate (30 ml×2). The extract waswashed with saturated brine, dried (anhydrous magnesium sulfate) andevaporated under reduced pressure to give the objective substance (0.52g, 100%).

¹H-NMR (CDCl₃)δ: 2.55 (1H, dd, J=13.8, 9.9 Hz), 2.98 (1H, dd, J=13.8,3.0 Hz), 3.22-3.36 (1H, m), 4.63 (1H, d, J=5.1 Hz), 7.02-7.12 (2H, m),7.30-7.42 (2H, m), 7.52-7.70 (2H, m), 7.85 (1H, s), 7.90 (1H, d, J=8.4Hz). IR ν max^(KBr)cm⁻¹: 1603, 1508, 1431, 1366.

2)N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-{3-[(trifluoromethyl)sulfonyl]benzyl}ethyl)-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-{3-[(trifluoromethyl)sulfonyl]phenyl}propan-1-ol(260 mg, 0.69 mmol) in acetonitrile (20 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (130 mg, 0.69mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198mg, 1.03 mmol) and 1-hydroxybenzotriazdle hydrate (105 mg, 0.69 mmol),and the mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization fromethyl acetate-hexane gave the objective substance (252 mg, 67%).

¹H-NMR (CDCl₃)δ: 1.90-2.06 (2H, m), 2.12-2.26 (2H, m), 2.60-2.70 (2H,m), 2.90-3.20 (3H, m), 4.60-4.80 (1H, m), 5.04 (1H, s), 5.82-5.98 (2H,m), 6.13 (1H, d, J=11.8 Hz), 6.95 (1H, dd, J=7.4, 1.8 Hz), 7.00-7.20(4H, m), 7.40-7.50 (2H, m), 7.52-7.64 (1H, m), 7.70 (1H, d, J=7.6 Hz),7.81 (1H, s), 7.89 (1H, d, J=7.8 Hz). IR ν max^(KBr)cm⁻¹: 1638, 1508,1449, 1366. mp 156-157° C. Anal. Calcd for C₂₈H₂₅NO₄SF₄: C, 61.42; H,4.60; N, 2.56. Found: C, 61.25; H, 4.57; N, 2.57.

Example 2814-fluoro-N-((1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-{3-[(trifluoromethyl)sulfonyl]benzyl}ethyl)-1-naphthamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-{3-[(trifluoromethyl)sulfonyl]phenyl}propan-1-ol(260 mg, 0.69 mmol) in acetonitrile (20 ml) were added4-fluoronaphthalenecarboxylic acid (131 mg, 0.69 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg,1.03 mmol) and 1-hydroxybenzotriazole hydrate (105 mg, 0.69 mmol), andthe mixture was stirred overnight at room temperature. The reactionsolution was diluted with water (100 ml) and extracted with ethylacetate (100 ml×2). The extract was washed successively with water andsaturated brine, dried (anhydrous magnesium sulfate) and evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization fromethyl acetate-hexane gave the objective substance (218 mg, 58%).

¹H-NMR (CDCl₃)δ: 2.84-3.20 (3H, m), 4.70-4.86 (1H, m), 5.09 (1H, s),6.10 (1H, d, J=9.0 Hz), 6.96-7.24 (4H, m), 7.40-7.62 (5H, m), 7.64-7.80(2H, m), 7.84-7.94 (2H, m), 8.08 (1H, d, J=7.6 Hz). IR ν max^(KBr)cm⁻¹:1642, 1626, 1601, 1514, 1369. mp 157-158° C. Anal. Calcd forC₂₇H₂₀NO₄SF₅: C, 59.01; H, 3.67; N, 2.55. Found: C, 58.88; H, 3.64; N,2.53.

Example 282N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-(3-isopropoxybenzyl)ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1) ethyl 3-isopropyloxybenzoate

To a solution of ethyl 3-hydroxybenzoate (15.2 g, 0.10 mol) inN,N-dimethylformamide (100 ml) were added isopropyl bromide (12.1 ml,0.13 mol) and sodium iodide (19.5 g, 0.13 mol), and the mixture wasstirred at 70° C. for 15 hrs. To the reaction solution was added water(500 ml), and the mixture was extracted with ethyl acetate (500,200 ml).The extract was washed with water, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel chromatography (hexane:ethyl acetate=10:1) to give theobjective substance (12.4 g, 64%) as an oil.

¹H-NMR (CDCl₃)δ: 1.35(6H, d, J=6.2 Hz), 3.90(3H, s), 4.55-4.65(1H, m),7.07(1H, dd, J=8.2, 1.8 Hz), 7.33(1H, t, J=8.2 Hz), 7.50-7.70(2H, m).

2) 3-isopropyloxybenzyl alcohol

To a solution of ethyl 3-isopropyloxybenzoate (12.0. g, 61.8 mmol) intetrahydrofuran (100 ml) was added lithium aluminum hydride (3.52 g,92.7 mmol) by small portions under ice-cooling. The mixture was stirredat room temperature for 1 hr. and water (10 ml) was added underice-cooling to allow decomposition. Insoluble material was filtered offand the solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography (hexane:ethyl acetate=3:1) to givethe objective substance (10.0 g, 97%) as an oil.

¹H-NMR (CDCl₃) δ: 1.34(6H, d, J=6.4 Hz), 4.50-4.65(1H, m), 4.66(1H, d,J=6.2 Hz), 6.78-6.90(1H, m), 6.90-7.00(2H, m), 7.26(1H, t, J=8.2 Hz).

3) ethyl 3-(4-fluorophenyl)-3-oxo-2-[3-(isopropyloxy)benzyl]propanoate

To a solution of 3-isopropyloxybenzyl alcohol (7.31 g, 44 mmol) in ethylacetate (50 ml) were added under ice-cooling methanesulfonyl chloride(3.56 ml, 46 mmol) and triethylamine (6.69 ml, 48 mmol), and the mixturewas stirred at room temperature for 2.5 hrs. Insoluble material wasfiltered off, and the solvent was evaporated under reduced pressure togive mesylate.

To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropanoate (8.41 g, 40mmol) in dimethoxyethane (50 ml) was added sodium hydride (1.60 g, 60%in oil, 40 mmol) under ice-cooling, and the mixture was stirred for 1hr. To the solution was dropwise added a solution of the mesylateobtained above in dimethoxyethane (20 ml), and the mixture was stirredat room temperature for 10 hrs. To the reaction solution was added water(200 ml), and the mixture was extracted with ethyl acetate (200 ml). Theextract was washed with water, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. The residue was purified bysilica gel chromatography (hexane:ethyl acetate=10:1-5:1) to give theobjective substance (12.5 g, 87%).

IR ν max^(Neat)cm⁻¹: 1736, 1688, 1599, 1508, 1258, 1233, 1157. ¹H-NMR(CDCl₃) δ: 1.13(3H, t, J=7.2 Hz), 1.30(6H, d, J=6.2 Hz), 3.28(2H, d,J=7.4 Hz), 4.15(2H, q, J=7.2 Hz), 4.57(1H, d, J=7.8 Hz), 4.40-4.60(1H,m), 6.60-6.80(3H, m), 7.00-7.25(3H, m), 7.90-8.10(2H, m).

4) ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(isopropyloxy)benzyl]propanoate

To a suspension of anhydrous zinc chloride (9.12 g, 67.0 mmol) indiethyl ether (100 ml) was added sodium borohydride (5.07 g, 134 mmol)by small portions, and the mixture was stirred for 2 hrs. Insolublematerial was filtered off, and washed with diethyl ether. The filtratewas ice-cooled, and to the filtrate was added a solution of ethyl3-(4-fluorophenyl)-3-oxo-2-[3-(isopropyloxy)benzyl]propanoate (12.0 g,33.5 mmol) in diethyl ether (20 ml). The mixture was stirred at roomtemperature for 2 hrs. and ice-cooled again. 1N Hydrochloric acid wasadded to stop the reaction. The mixture was washed with water, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was purified by silica gel chromatography(hexane:ethylacetate=10:1) to give the objective substance (10 g, 83%) as a colorlessoil

IR ν max^(Neat)cm⁻¹: 1728, 1603, 1510, 1260, 1157. ¹H-NMR (CDCl₃) δ:0.94(3H, t, J=7.2 Hz), 1.30(6H, d, J=6.2 Hz), 2.80-3.00(4H, m), 3.89(2H,d, J=7.2 Hz), 4.40-4.60(1H, m), 5.01(1H, s), 6.58-6.75(3H, m),6.98-7.20(3H, m), 7.30-7.45(2H, m).

5)(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(isopropyloxy)benzyl]propanoicacid

To a solution-of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(isopropyloxy)benzyl]propanoate(9.8 g, 27.2 mmol) in methanol (50 ml) was added 2N aqueous sodiumhydroxide solution (27.2 ml, 54.4 mmol), and the mixture was stirred atroom temperature for 3 hrs. The reaction solution was acidified with 6Nhydrochloric acid (100 ml). The mixture was extracted with ethyl acetate(200, 100 ml). The extract was washed with water, dried over anhydrousmagnesium sulfate, and evaporated under reduced pressure. The residuewas crystallized from hexane to give the objective substance (7.44 g,82%).

mp 101-102° C. IR ν max^(KBr)cm⁻¹: 1694, 1514, 1451, 1292, 1260, 1229,1152, 1119. Anal. Calcd for C₁₉H₂₁FO₄ (MW332.37) Calcd: C, 68.66; H,6.37 Found: C, 68.52; H, 6.37 ¹H-NMR (CDCl₃) δ: 1.29(6H, d, J=6.2 Hz),2.80-3.15(3H, m), 4.40-4.60(1H, m), 5.00-5.10(1H, m), 6.55-6.80(3H, m),6.95-7.20(3H, m), 7.30-7.45(2H, m).

6)(4RS,5SR)-5-(4-fluorophenyl)-4-[3-(isopropyloxy)benzyl]-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(isopropyloxy)benzyl]propanoicacid (7.14 g, 21.5 mmol) in tetrahydrofuran (100 ml) were addeddiphenylphosphoryl azide (6.0 ml, 27.9 mmol) and triethylamine (4.19 ml,30.1 mmol), and the mixture was stirred at room temperature for 1 hr.The mixture was heated under reflux for 5 hrs. and concentrated underreduced pressure. The saturated aqueous sodium hydrogen carbonate (100ml) was added and the mixture was extracted with ethyl acetate (200 ml).The extract was washed with water, dried over anhydrous magnesiumsulfate and evaporated under reduced pressure. The residue was purifiedby silica gel chromatography (hexane:ethyl acetate=4:1-2:1) to givethe-objective substance (14.7 g, 91%).

mp 114-115° C. IR ν max^(KBr)cm⁻¹: 1738, 1582, 1514, 1385, 1248, 1227,1157. Anal. Calcd for C₁₉H₂₀FNO₃ (MW329.36) Calcd: C, 69.29; H, 6.12; N,4.25. Found: C, 69.27; H, 6.16; N, 4.26. ¹H-NMR (CDCl₃) δ: 1.32(6H, d,J=6.0 Hz), 2.05-2.35(2H, m), 4.15-4.60(1H, m), 4.96(1H, brs), 5.78(1H,d, J=7.6 Hz), 6.50-6.65(2H, m), 6.70-6.80(1H, m), 7.00-7.25(3H, m),7.30-7.45(2H, m).

7)(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(isopropyloxy)phenyl]-1-propanol

To a solution of(4RS,5SR)-5-(4-fluorophenyl)-4-[3-(isopropyloxy)benzyl]-1,3-oxazolidin-2-one(5.85 g, 17.8 mmol) in ethanol (30 ml) was added 8N aqueous sodiumhydroxide solution (8.9 ml, 71.0 mmol), and the mixture was heated underreflux for 5 hrs. The reaction solution-was concentrated under reducedpressure. To the solution was added water (100 ml) and the mixture wasextracted with ethyl acetate (100 ml×2). The extract was washed withwater, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was crystallized from hexane-diethyl etherto give the objective substance (5.0 g, 93%).

mp 98-99° C. IR ν max^(KBr)cm⁻¹: 3364, 1605, 1582, 1508, 1252, 1211,1154, 1044. Anal. Calcd for C₁₈H₂₂FNO₂ (MW303.37) Calcd: C, 71.26; H,7.31; N, 4.62. Found: C, 71.30; H, 7.46; N, 4.55. ¹H-NMR (CDCl₃) δ:1.32(6H, d, J=6.0 Hz), 2.28(1H, dd, J=13.6, 10.2 Hz), 2.73(1H, dd,J=13.6, 3.0 Hz), 3.20-3.40(1H, m), 4.45-4.60(1H, m), 4.67(1H, d, J=4.8Hz), 6.60-6.80(3H, m), 7.00-7.45(5H, m).

8)N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-(3-isopropoxybenzyl)ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(isopropyloxy)phenyl]-1-propanol(0.46 g, 1.5 mmol) and 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylicacid (0.34 g, 1.8 mmol) in acetonitrile (20 ml) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g, 2.1mmol) and 1-hydroxybenzotriazole hydrate (0.32 g, 2.1 mmol), and themixture was stirred at room temperature for 5 hrs. To the reactionsolution was added water (100 ml), and the mixture was extracted with-ethyl acetate (100 ml×2). The extract was washed with water, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel chromatography (hexane:ethylacetate=4:1) to give the objective substance (0.55 g, 77%) as crystals.

mp 161-162° C. IR ν max^(KBr)cm⁻¹: 3274, 1638, 1510, 1258, 1225, 833.Anal. Calcd for C₃₀H₃₂FNO₃ (MW473.58) Calcd: C, 76.08; H; 6.81; N, 2.96.Found: C, 76.10; H, 6.73; N, 2.89. ¹H-NMR (CDCl₃) δ: 1.30(6H, d, J=6.0Hz), 1.90-2.10(2H, m), 2.10-2.30(2H, m), 2.60-2.80(2H, m), 2.96(1H, dd,J=14.0, 4.4 Hz), 4.10(1H, d, J=4.4 Hz), 4.40-4.60(1H, m), 4.60-4.80(1H,m), 5.00-5.10(1H, m), 5.66(1H, d, J=7.8 Hz), 5.90-6.00(1H, m), 6.40(1H,d, J=11.8 Hz), 6.65-6.85(3H, m), 6.95-7.25(7H, m), 7.35-7.50(2H, m).

Example 2834-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-(3-isopropoxybenzyl)ethyl]-1-naphthamide

To a solution of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(isopropyloxy)phenyl]-1-propanol(0.46 g, 1.5 mmol) and 4-fluoronaphthalene-1-carboxylic acid (0.34 g,1.8 mmol) in acetonitrile (20 ml) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g, 2.1mmol) and 1-hydroxybenzotriazole hydrate (0.32 g, 2.1 mmol), and themixture was stirred at room temperature for 5 hrs. To the reactionsolution was added water (100 ml), and the mixture was extracted withethyl acetate (100 ml×2). The extract was washed with water, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel chromatography (chloroform:ethylacetate=10:1) to give the objective substance (0.65 g, 91%) as crystals.

mp 190-191° C. IR ν max^(KBr)cm⁻¹: 3281, 1640, 1624, 1539, 1514, 1256,1229. Anal. Calcd for C₂₉H₂₇F₂NO₃ (MW475.53) Calcd: C, 73.25; H, 5.72;N, 2.95. Found: C, 72.87; H, 5.57; N, 2.84. ¹H-NMR (CDCl₃-DMSO-d₆ (1drop)) δ: 1.26(6H, d, J=6.0 Hz), 2.70-3.00(2H, m), 4.40-4.60(1H, m),4.65-4.85(1H, m), 4.95-5.10(2H, m), 6.70-6.85(3H, m), 6.85-7.60(10H, m),7.74(1H, d, J=6.8 Hz), 8.06(1H, d, J=7.6 Hz).

Example 2844-fluoro-N-[(1RS,2SR)-1-(3-tert-butyloxybenzyl)ethyl]-2-(4-fluorophenyl)-2-hydroxy-1-naphthamide

1) ethyl 3-tert-butyloxybenzoate

To a solution of ethyl 3-hydroxybenzoate (20 g, 0.13 mol) indichloromethane (200 ml) were added isobutene (about 30 g) and conc.sulfuric acid (0.5 ml), and the mixture was left for 2 days. Thereaction solution was washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel chromatography (hexane:ethyl acetate=10:1) to give the objectivesubstance (17.3 g, 63%) as an oil.

¹H-NMR (CDCl₃) δ: 1.37(9H, s, Bu^(t)), 3.91(3H, s), 7.15-7.25(1H, m),7.33(1H, t, J=7.9 Hz), 7.65-7.70(1H, m), 7.76(1H, d, J=7.9 Hz).

2) 3-tert-butyloxybenzyl alcohol

To a solution of ethyl 3-tert-butyloxybenzoate (16.7 g, 80 mmol) intetrahydrofuran (100 ml) was added lithium aluminum hydride (4.55 g, 120mmol) by small portions under ice-cooling. The mixture was stirred atroom temperature for 1 hr. and water (10 ml) was added under ice-coolingto allow decomposition. Insoluble material was filtered off and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography (hexane:ethyl acetate=3:1-2:1) to give theobjective substance (12.8 g, 88%) as an oil.

¹H-NMR (CDCl₃) δ: 1.35(9H, s, Bu^(t)), 4.66(2H, d, H=6.0 Hz), 6.93(1H,m), 7.00(1H, brs), 7.07(1H, d, J=7.4 Hz), 7.25(1H, t, J=7.4 Hz).

3) ethyl 3-(4-fluorophenyl)-2-[3-(tert-butyloxy)benzyl]-3-oxopropanoate

To a solution of 3-tert-butyloxybenzyl alcohol (10.8 g, 60 mmol) inethyl acetate (100 ml) were added methanesulfonyl chloride (4.88 ml, 63mmol) and triethylamine (9.2 ml, 66 mmol) under ice-cooling, and themixture was stirred at room temperature for 1 hr. Insoluble material wasfiltered off, and the solvent was evaporated under reduced pressure togive mesylate.

To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropanoate (12.6 g., 60mmol) in dimethoxyethane (100 ml) was added sodium hydride (2.4 g, 60%in oil, 60 mmol) under ice-cooling, and the mixture was stirred for 10min. To the solution was dropwise added a solution of mesylate obtainedabove in dimethoxyethane (20 ml), and the mixture was stirred at roomtemperature for 4 hrs. To the reaction solution was added water (200ml), and the mixture was extracted with ethyl acetate (200 ml×2). Theextract was washed with water, dried over anhydrous magnesium-sulfateand evaporated under reduced pressure. The residue was purified bysilica gel chromatography (hexane:ethyl acetate=10:1) to give theobjective substance (20.1 g, 90%).

IR ν max^(Neat)cm⁻¹: 1740, 1686, 1599, 1508, 1485, 1366, 1233, 1152.¹H-NMR (CDCl₃) δ: 1.13(3H, t, J=7.0 Hz), 1.28(9H, s, Bu^(t)), 3.29(2H,d, J=7.4 Hz), 4.10 (2H, q, J=7.0 Hz), 4.56(1H, t, J=7.4 Hz),6.67-6.90(2H, m), 6.95(1H, d, J=7.6 Hz), 7.05-7.20(3H, m), 7.90-8.05(2H,m).

4) ethyl(2RS,3RS)-2-[3-(tert-butyloxy)benzyl]-3-(4-fluorophenyl)-3-hydroxypropanoate

To a suspension of anhydrous zinc chloride (8.17 g, 60 mmol) in diethylether (100 ml) was added sodium borohydride (4.54 g, 120 mmol) by smallportions, and the mixture was stirred for 2 hrs. Insoluble material wasfiltered off and washed with diethyl ether. The filtrate was ice-cooled,and a solution of ethyl3-(4-fluorophenyl)-2-[3-(tert-butyloxy)benzyl]-3-oxopropanoate (10.8 g,30 mmol) in diethyl ether (20 ml) was added. The mixture was stirred atroom temperature for 1 hr., ice-cooled again and water was added to stopthe reaction. The mixture was washed with 5% aqueous potassium hydrogensulfate solution and water, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel chromatography (hexane:ethyl acetate=10:1) to give the objectivesubstance (8.9 g, 79%) as a colorless oil. IR ν max^(Neat)cm⁻¹: 1728,1605, 1510, 1260, 1225, 1179, 1154. ¹H-NMR (CDCl₃) δ: 0.93(3H, t, J=7.2Hz), 1.31(9H, s, Bu^(t)), 2.90-3.05(3H, m), 3.87(2H, d, J=7.2 Hz),4.95-5.10(1H, m), 6.70-6.80(1H, m), 6.80(1H, d, J=7.8 Hz), 7.00-7.20(3H,m), 7.30-7.45(2H, m).

5)(4RS,5SR)-4-[3-(tert-butyloxy)benzyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one

To a solution of ethyl(2RS,3RS)-2-[3-(tert-butyloxy)benzyl]-3-(4-fluorophenyl)-3-hydroxypropanoate(8.8 g, 23.5 mmol) in methanol (100 ml) was added 2N aqueous sodiumhydroxide solution (23.5 ml, 47 mmol), and the mixture was stirred atroom temperature for 3 hrs. The reaction solution was acidified with 5%aqueous potassium hydrogen sulfate solution (100 ml). The mixture wasextracted with ethyl acetate (200 ml). The extract was washed withwater, dried over anhydrous magnesium sulfate, and evaporated underreduced pressure. The residue was crystallized from hexane to give(2RS,3RS)-2-[3-(tert-butyloxy)benzyl]-3-(4-fluorophenyl)-3-hydroxypropanoicacid.

To a solution of the compound obtained above in tetrahydrofuran (150 ml)were added diphenylphosphoryl azide (6.57 ml, 30.6 mmol) andtriethylamine (4.59 ml, 32.9 mmol), and the mixture was stirred at roomtemperature for 1 hr. Then, the mixture was heated under reflux for 2hrs., and concentrated under reduced pressure. Water (200 ml) was added,and the mixture was extracted with ethyl acetate (200 ml). The extractwas washed with water, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel: chromatography (hexane:ethyl acetate=3:1-2:1) to give the objectivesubstance (6.92 g, 86%). mp 131-132° C.

IR ν max^(KBr)cm⁻¹: 1742, 1603, 1514, 1364, 1240, 1223, 1148. Anal.Calcd for C₂₀H₂₂FNO₃ (MW343.40) Calcd: C, 69.95; H, 6.46; N, 4.08.Found: C, 69.96; H, 6.38; N, 4.11. ¹H-NMR (CDCl₃) δ: 1.33(9H, s,Bu^(t)), 2.10-2.40(2H, m), 4.15-4.30(1H, m), 4.91(1H, brs), 5.79(1H; d,J=7.8 Hz), 6.60-6.80(2H, m), 6.80-6.95(1H, m), 7.05-7.25(3H, m),7.30-7.50 (2H, m).

6)(1RS,2SR)-2-amino-3-[3-(tert-butyloxy)phenyl]-1-(4-fluorophenyl)-1-propanol

To a solution of(4RS,5SR)-4-[3-(tert-butyloxy)benzyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one(6.6 g, 19.2 mmol) in ethanol (30 ml) was added 8N aqueous sodiumhydroxide solution (9.6 ml, 76.9 mmol), and the mixture was heated underreflux for 4 hrs. The reaction solution was concentrated under reducedpressure. Water (150 ml) was added, and the mixture was extracted withethyl acetate (200 ml). The extract was washed with water, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was crystallized from hexane-diethyl ether to give the objectivesubstance (5.86 g, 96%).

mp 132-133° C. IR ν max^(KBr)cm⁻¹: 3362, 3295, 1601, 1582, 1507, 1485,1363, 1208, 1152, 1036. Anal. Calcd for C₁₉H₂₄FNO₂ (MW317.40) Calcd: C,71.90; H, 7.62; N, 4.41. Found: C, 71.69; H, 7.65; N, 4.35. ¹H-NMR(CDCl₃) δ: 1.33(9H, s, Bu^(t)), 2.29(1H, dd, J=14.0, 10.2 Hz), 2.74(1H,dd, J=14.0, 3.0 Hz), 3.20-3.35(1H, m), 4.66(1H, d, J=5.2 Hz),6.75-6.90(3H, m), 7.70-7.25 (3H, m), 7.30-7.45(2H, m).

7)4-fluoro-N-[(1RS,2SR)-1-(3-tert-butyloxybenzyl)ethyl]-2-(4-fluorophenyl)-2-hydroxy-1-naphthamide

To a solution of(1RS,2SR)-2-amino-3-[3-(tert-butyloxy)phenyl]-1-(4-fluorophenyl)-1-propanol(1.59 g, 5.0 mmol) and 4-fluoronaphthalene-1-carboxylic acid (1.14 g,6.0 mmol) in acetonitrile (30 ml) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.20 g, 7.0mmol) and 1-hydroxybenzotriazole hydrate (1.07 g, 7.0 mmol), and themixture was stirred at room temperature for 5 hrs. To the reactionsolution was added water (100 ml), and the mixture was extracted withethyl acetate (150 ml). The extract was washed with water, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel chromatography (chloroform:ethylacetate=10:1) to give the objective substance (2.27 g, 93%) as crystals.

mp 180-181° C. IR ν max^(KBr)cm⁻¹: 3420, 3312, 1644, 1539, 1508, 1223,1150. Anal. Calcd for C₃₀H₂₉F₂NO₃ (MW489.55) Calcd: C, 73.60; H, 5.97;N, 2.86. Found: C, 73.61; H, 6.00; N, 2.76. ¹H-NMR (CDCl₃) δ: 1.28(9H,s, Bu^(t)), 2.73(1H, dd, J=14.1, 10.6 Hz), 3.03(1H, dd, J=14.4, 4.4 Hz),3.90(1H, d, J=3.6 Hz), 4.70-4.90(1H, m), 5.00-5.15(1H, m), 5.85(1H, brd,J=4.4 Hz), 6.80-7.30(8H, m), 7.4-7.60(4H, m), 7.83(1H, d, J=8.0 Hz),8.08(1H, d, J=7.2 Hz).

Example 285N-[(1RS,2SR)-1-(3-tert-butyloxybenzyl)ethyl]-2-(4-fluorophenyl)-2-hydroxy-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-3-[3-(tert-butyloxy)phenyl]-1-(4-fluorophenyl)-1-propanol(0.48 g, 1.5 mmol) and 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylicacid (0.34 g, 1.8 mmol) in acetonitrile (20 ml) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g, 2.1mmol) and 1-hydroxybenzotriazole hydrate (0.32 g, 2.1 mmol) and themixture was stirred at room temperature for 5 hrs. To the reactionsolution was added water (100 ml) and the mixture was extracted withethyl acetate (150 ml). The extract was washed with water, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel chromatography (hexane:ethylacetate=4:1-3:1) to give the objective substance (0.63 g,. 86%) ascrystals.

mp 149-150° C. IR ν max^(KBr)cm⁻¹: 3303, 1638, 1537, 1512, 1443, 1256,1225, 1150, 1032. Anal. Calcd for C₃₁H₃₄FNO₃ (MW487.61) Calcd: C, 76.36;H, 7.03; N, 2.87. Found: C, 76.29; H, 7.20; N, 2.80. ¹H-NMR (CDCl₃) δ:1.30(9H, s, Bu^(t)), 1.90-2.10(2H, m), 2.10-2.30(2H, m), 2.60-2.80 (2H,m), 2.96(1H, dd, J=7.3, 4.4 Hz), 4.06(1H, d, J=4.0 Hz), 4.60-4.80(1H,m), 5.01(1H, t, J=3.7 Hz), 5.65(1H, brd, J=8.0 Hz), 5.90-6.05(1H, m),6.25(1H, d, J=11.4 Hz), 6.78-7.30 (9H, m), 7.30-7.50(2H, m).

Example 2864-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-(3-hydroxybenzyl)ethyl]-1-naphthamide

To a solution of4-fluoro-N-[(1RS,2SR)-1-(3-tert-butyloxybenzyl)ethyl]-2-(4-fluorophenyl)-2-hydroxy-1-naphthamide(0.30 g, 0.61 mmol) in tetrahydrofuran (10 ml) was added trifluoroaceticacid (5 ml), and the mixture was stirred at 50° C. for 2 hrs. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel chromatography (chloroform:ethyl acetate=5:1) togive the objective substance (0.18 g, 68%) as crystals.

mp 179-180° C. IR ν max^(KBr)cm⁻¹: 1644, 1601, 1537, 1512, 1262, 1231,1157, 1053. Anal. Calcd for C₂₆H₂₁F₂NO₃ (MW433.45) Calcd: C, 72.05; H,4.88; N, 3.23. Found: C, 71.61; H, 5.14; N, 3.07. ¹H-NMR (CDCl₃) δ:2.50-2.75(2H, m), 3.10-3.30(1H, m), 4.30-4.55(1H, m), 4.55-4.65 (1H, m),5.73(1H, d, J=4.4 Hz), 6.60-6.75(3H, m), 7.00-7.70(9H, m), 7.99(1H, d,J=7.6 Hz), 8.25-8.40(1H, m), 9.21(1H, s).

Example 287 benzylN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]carbamate

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(0.278 g, 0.769 mmol) and sodium hydrogen carbonate (0.13 g, 1.54 mmol)in tetrahydrofuran (10 ml), benzyl chlorocarbonate (0.12 ml, 0.85 mmol)was-added at room temperature and the mixture was stirred as it was for3 hrs. The reaction solution was diluted with ethyl acetate, washed withaqueous sodium hydrogen carbonate solution, dried over anhydrousmagnesium sulfate and passed through silica gel. The solvent wasevaporated under reduced pressure and the obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white crystal yield 0.344 g, 90% mp 136-137° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.64-2.91 (3H, m), 4.09-4.20 (1H, m), 4.82 (1H, br d, J=9.2 Hz),4.85-5.04 (3H, m), 5.88 (1H, tt, J=2.9 Hz, 53.1 Hz), 6.96-7.09 (5H, m),7.21-7.39 (8H, m); IR (KBr) 3326, 1692, 1545, 1198, 1115 cm⁻¹; Anal.Calcd for C₂₅H₂₂F₅NO₄: C, 60.61; H, 4.48; N, 2.83. Found: C, 60.81; H,4.53; N, 2.99.

Example 288N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,6-dimethyl-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1) ethyl (E)-4,4-dimethyl-5-phenyl-2-pentenoate

A suspension (17.8 g, 445 mmol) of 60% sodium hydride in liquid paraffinwas suspended in toluene (300 ml), and a solution of ethyldiethylphosphonoacetate (99.8 g, 445 mmol) in toluene (50 ml) was addedat room temperature. The mixture was stirred for 30 min. A solution of2,2-dimethyl-3-phenylpropanal (see Tetrahedron Lett., 1273-1275 (1973))(60.16 g, 370.8 mmol) in toluene (50 ml) was dropwise added, and themixture was stirred at room temperature for 2 hrs. The reaction solutionwas poured into water, and the mixture was extracted twice with diethylether. The recovered organic layer was dried over anhydrous magnesiumsulfate and the solvent was evaporated under reduced pressure. Theobtained crude product was purified by silica gel column chromatography(hexane/ethyl acetate=20/1-9/1) to give the objective substance.

colorless liquid yield 55.97 g, 65% ¹H-NMR (CDCl₃, 200 MHz) δ 1.06 (6H,s), 1.29 (3H, t, J=7.2 Hz), 2.66 (2H, s), 4.19 (2H, q, J=7.1 Hz), 5.63(1H, d, J=16.2 Hz), 7.03 (1H, d, J=16.2 Hz), 7.06-7.10 (2H, m),7.20-7.38 (3H, m); IR (neat) 2963, 1717, 1310, 1167, 1038, 702 cm⁻¹

2) ethyl 4,4-dimethyl-5-phenylpentanoate

A solution of ethyl (E)-4,4-dimethyl-5-phenyl-2-pentenoate (55.97 g,240.9 mmol) in ethanol (150 ml) was hydrogenated using 10%palladium/carbon (containing water by 50%) (5 g) as a catalyst at roomtemperature overnight under normal pressure. The recovered catalyst ofthe reaction solution was filtered off and the catalyst was washed withethanol. The recovered solvent of the filtrate was evaporated underreduced pressure. The obtained crude product was purified by silica gelcolumn chromatography (hexane/ethyl acetate=15/1-9/1) to give theobjective substance.

colorless liquid yield 45.47 g, 81% ¹H-NMR (CDCl₃, 200 MHz) δ 0.86 (6H,s), 1.26 (3H, t, J =7.2 Hz), 1.56-1.64 (2H, m), 2.30-2.38 (2H, m), 2.51(2H, s), 4.13 (2H, q, J=7.1 Hz), 7.10-7.15 (2H, m), 7.20-7.32 (3H, m);IR (neat) 2961, 1736, 1171, 704 cm⁻¹

3) 4,4-dimethyl-5-phenylpentanoic acid

A mixture of ethyl 4,4-dimethyl-5-phenylpentanoate (45.47 g, 194.0 mmol)and sodium hydroxide (15.5 g, 388 mmol), water (200 ml), methanol (200ml) and tetrahydrofuran (100 ml) was stirred overnight at roomtemperature. The reaction solution was concentrated under reducedpressure and diluted with water. After washing with diethyl ether, themixture was acidified with conc. hydrochloric acid and extracted twicewith ethyl acetate. The recovered organic layer was dried over anhydroussodium sulfate and the solvent was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (ethyl acetate) to give the objective substance.

colorless liquid yield 38.35 g, 96% ¹H-NMR (CDCl₃, 200 MHz) δ 0.88 (6H,s), 1.57-1.65 (2H, m), 2.35-2.43 (2H, m), 2.52 (2H, s), 7.10-7.15 (2H,m), 7.21-7.32 (3H, m); IR (neat) 3100-2850, 1715, 1452, 1416, 1302, 702cm⁻¹

4) 8,8-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one

To a solution of 4,4-dimethyl-5-phenylpentanoic acid (38.30 g, 185.7mmol) and N,N-dimethylformamide (0.1 ml) in tetrahydrofuran (150 ml) wasdropwise added oxalyl chloride (24.3 ml, 279 mmol) at room temperature,and the mixture was stirred as it was at room temperature for 0.5 hr.The solvent of the reaction mixture was evaporated under reducedpressure to give acid chloride as a yellow liquid. While stirring asuspension of aluminum chloride (49.5 g, 371 mmol) in methylene chloride(250 ml), absolution of the acid-chloride obtained above in methylenechloride (800 ml) was dropwise added over 2 days. While ice-cooling thereaction solution, water was added to terminate the reaction. Themethylene chloride layer was separated and the aqueous layer wasextracted with diethyl ether. The recovered organic layer was dried overanhydrous magnesium sulfate and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate=15/1-6/1) to give the objectivesubstance.

yellow liquid yield 29.55 g, 85% ¹H-NMR (CDCl₃, 200 MHz) δ 1.02 (6H, s),1.45-1.51 (2H, m), 2.62 (2H, s), 2.63-2.69 (2H, m), 7.12 (1H, dd, J=1.0Hz, 7.2 Hz), 7.31 (1H, dt, J=1.5 Hz, 7.5 Hz), 7.43 (1H, dt, J=1.6 Hz,7.5 Hz), 7.72 (1H, dd, J=1.4 Hz, 7.4 Hz); IR (neat) 2953, 2928, 1682,1601, 1468, 1289, 770 cm⁻¹

5) 8,8-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol

To a solution of8,8-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one (29.20 g,155.1 mmol) in methanol (150 ml) was added sodium borohydride (5.87 g,155 mmol) by small portions under ice-cooling, and the mixture wasstirred at room temperature for 1 hr. The reaction solution was dilutedwith water and extracted twice with ethyl acetate. The recovered organiclayer was-dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (hexane/ethyl acetate=9/1-6/1) to givethe objective substance.

yellow liquid yield 28.96 g, 98% ¹H-NMR (CDCl₃, 200 MHz) δ 0.72 (3H, s),0.94 (3H, s), 1.54-1.97 (4H, m), 1.78 (1H, d, J=4.0 Hz), 2.67 (2H, brs), 4.85-4.93 (1H, m), 7.02 (1H, dd, J=1.6 Hz, 7.2 Hz), 7.11-7.23 (2H,m), 7.42 (1H, d, J=7.0 Hz); IR (neat) 3353, 2951, 2928, 1456, 1044, 756cm⁻¹

6)4-(hydroxymethyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol

To a solution of8,8-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol (28.72 g,150.9 mmol) and N,N,N′,N′-tetramethylethylenediamine (50.1 ml, 332 mmol)in hexane (200 ml) was added a solution (208 ml, 332 mmol) of 1.6 Mn-butyllithium in hexane under ice-cooling and the mixture was stirredat 35° C. overnight. After cooling the reaction mixture at −78° C.,crushed dry ice (50 g) was added, and the mixture was warmed to roomtemperature under stirring. The reaction solution was diluted with wateracidified with conc. hydrochloric acid and washed three times with ethylacetate. The recovered organic layer was dried over anhydrous magnesiumsulfate and the solvent was evaporated under reduced pressure. Theobtained crude product was passed through silica gel columnchromatography (hexane/ethyl acetate=6/1) to give a crude product (31.00g) of7,7-dimethyl-7,8,9,9a-tetrahydrocyclohepta[cd][2]benzofuran-2(6H)-one asa yellow wet solid.

To a suspension of lithium aluminum hydride (5.73 g, 151 mmol) intetrahydrofuran (200 ml) was dropwise added a solution of the solidobtained above in tetrahydrofuran (100 ml) under ice-cooling, and themixture was stirred at room temperature for 1 hr. After ice-cooling thereaction solution, water (6 ml), 15% aqueous sodium hydroxide solution(6 ml) and water (15 ml) were successively added dropwise to decomposeexcess lithium aluminum hydride. The mixture was stirred as it was atroom temperature for 2 hrs. The resulting precipitate was removed byfiltration, and the precipitate was washed with ethyl acetate. Thesolvent of the recovered filtrate was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=6/1−1/2). Crystallization fromhexane gave the objective substance.

white crystal yield 19.15 g, 58% mp 107-108° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 0.76. (3H, s), 0.99 (3H, s), 1.16-1.28 (1H, m), 1.68-1.82 (1H, m),1.91-2.03 (2H, m), 2.30 (1H, d, J=13.6 Hz), 2.63 (1H, br t, J=5.3 Hz),2.93 (1H, br s), 3.22 (1H, d, J=13.8 Hz), 4.58 (1H, dd, J=5.3 Hz, 11.9Hz), 4.85 (1H, dd, J=5.7 Hz, 11.9 Hz), 5.24-5.32 (1H, m), 7.00-7.06 (1H,m), 7.08-7.17 (2H, m); IR (KBr) 3312, 2951, 1402, 1016, 997, 762 cm⁻¹;Anal. Calcd for C₁₄H₂₀O₂: C, 76.33; H, 9.15. Found: C, 76.37; H, 9.28.

7)4-[[[tert-butyl(dimethyl)silyl]oxy]methyl]-8,8-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol

To a solution of4-(hydroxymethyl)-8,8-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol(18.87 g, 85.65 mmol), 4-N,N-dimethylaminopyridine (0.5 g) andtriethylamine (14.3 ml, 103 mmol) in tetrahydrofuran (100 ml) was addedtert-butyldimethylchlorosilane (14.2 g, 94.2 mmol) at room temperature,and the mixture was stirred as it was overnight. The reaction solutionwas poured into water, and extracted twice with ethyl acetate. Therecovered organic layer was dried over anhydrous magnesium sulfate andthe solvent was evaporated under reduced pressure. The obtained crudeproduct was purified by silica gel column chromatography (hexane/ethylacetate=15/1-9/1) to give the objective substance.

colorless liquid yield 28.90 g, 100% ¹H-NMR (CDCl₃, 200 MHz) δ 0.08 (3H,s), 0.11 (3H, s), 0.76 (3H, s), 0.90 (9H, s), 0.99 (3H, s), 1.16-1.30(1H, m), 1.67-1.80 (1H, m), 1.88-2.05 (2H, m), 2.30 (1H, d, J=13.6 Hz),3.02 (1H, br s), 3.23 (1H, d, J=14.0 Hz), 4.64 (1H, d, J=11.8 Hz), 4.94(1H, d, J=12.0 Hz), 5.23-5.31 (1H, m), 6.98-7.04 (1H, m), 7.06-7.15 (2H,m); IR (neat) 3391, 2951, 2928, 2857, 1470, 1254, 1076, 837, 775 cm⁻¹

8) tert-butyl(6,6-dimethyl-6,7-dihydro-5H-benzo[a]cyclohepten-1-ylmethoxy)dimethylsilane

To a solution of4-[[[tert-butyl(dimethyl)silyl]oxy]methyl]-8,8-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol(28.90 g, 86.38 mmol), triethylamine (24.1 ml, 173 mmol) and4-N,N-dimethylaminopyridine (1.06 g, 8.64 mmol) in acetonitrile (100 ml)was dropwise added a solution of methanesulfonyl chloride (14.8 g, 130mmol) in acetonitrile (10 ml) under ice-cooling. Lithium chloride (5.49g, 130 mmol) was added thereto, and the mixture was stirred at roomtemperature for 6 hrs. The reaction solution was poured into water andextracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained residue was dissolved inN,N-dimethylformamide (100 ml), and 1,8-diazabicyclo[5.4.0]-7-undecene(25.8 ml, 173 mmol) was added. The mixture was stirred at 80° C.overnight. The reaction solution was-poured into water and extractedtwice with ethyl acetate. The recovered organic layer was dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The obtained crude product was purified by silica gelcolumn chromatography (hexane/ethyl acetate=15/1) to give the objectivesubstance.

pale-yellow liquid yield 10.25 g, 38% ¹H-NMR (CDCl₃, 200 MHz) δ 0.09(6H, s), 0.94 (9H, s), 1.01 (6H, s), 1.65 (2H, d, J=7.0 Hz), 2.32 (2H,s), 4.71 (2H, s), 6.25 (1H, td, J=7.0 Hz, 10.7 Hz), 6.64 (1H, d, J=10.8Hz), 7.07 (1H, d, J=8.8 Hz), 7.17 (1H, t, J=7.5 Hz), 7.37 (1H, d, J=8.0Hz); IR (neat) 2953, 2928, 1464, 1256, 1111, 1074, 837, 775 cm⁻¹

9) 6,6-dimethyl-6,7-dihydro-5H-benzo[a]cyclohepten-1-ylmethanol

To a solution of tert-butyl(6,6-dimethyl-6,7-dihydro-5H-benzo[a]cyclohepten-1-ylmethoxy)dimethylsilane(7.306 g, 23.08 mmol) in tetrahydrofuran (30 ml) was added a solution of1.0 M tetrabutylammonium fluoride in tetrahydrofuran (27.7 ml, 27.7mmol) at room temperature, and the mixture was stirred at roomtemperature for 15 min. The reaction solution was poured into water, andextracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous magnesium sulfate and the solvent was evaporatedunder reduced pressure. The obtained crude product was purified bysilica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to givethe objective substance.

colorless liquid yield 4.484 g, 96% ¹H-NMR (CDCl₃, 200 MHz) δ 1.02 (6H,s), 1.59 (1H, t, J=5.9 Hz), 1.67 (2H, d, J=7.4 Hz), 2.35 (2H, s), 4.70(2H, d, J=6.2 Hz), 6.32 (1H, td, J=7.0 Hz, 10.6 Hz), 6.79 (1H, d, J=10.6Hz), 7.11-7.31 (3H, m); IR (neat) 3318, 2951, 1454, 774 cm⁻¹

10) 6,6-dimethyl-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid

To a solution of6,6-dimethyl-6,7-dihydro-5H-benzo[a]cyclohepten-1-ylmethanol (4.429 g,21.90 mmol) in acetone (100 ml) was dropwise added slowly a solution ofchromic anhydride (5.47 g, 53.7 mmol) and conc. sulfuric acid (4 ml) inwater (15 ml) under ice-cooling. After completion of the dropwiseaddition, the mixture was stirred at room temperature for 1.5 hrs. Thereaction solution was ice-cooled again and isopropanol (20 ml) wasadded. The mixture was stirred as it was for 0.5 hr. and acetone of thereaction solution was evaporated under reduced pressure. The residue wasdiluted with ethyl acetate, washed three times with water and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the obtained residue was crystallized from ethylacetate-hexane to give the objective substance.

yellow crystal yield 3.087 g, 65% mp 132-134° C.; ¹H-NMR (CDCl₃, 200MHz) δ 1.03 (6H, s), 1.66 (2H, d, J=7.4 Hz), 2.37 (2H, s), 6.33 (1H, td,J=7.3 Hz, 10.6 Hz), 7.23 (1H, d, J=10.6 Hz), 7.26 (1H, t, J=7.5 Hz),7.39 (1H, dd, J=1.3 Hz, 7.5 Hz), 8.00 (1H, dd, J=1.5 Hz, 7.6 Hz); IR(KBr) 3050-2550, 1682, 1464, 1451, 1308, 1279, 775 cm⁻¹; Anal. Calcd forC₁₄H₁₆O₂: C, 77.75; H, 7.46. Found: C, 77.97; H, 7.57.

11)N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,6-dimethyl-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(0.367 g, 1.016 mmol),6,6-dimethyl-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (0.22g, 1.02 mmol) and 1-hydroxybenzotriazole hydrate (0.16 g, 1.02 mmol) inacetonitrile. (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.19 g, 1.02 mmol) was added, and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solution,dried over anhydrous magnesium sulfate and passed through silica gel.The solvent was evaporated under reduced pressure. The obtained residuewas crystallized from diisopropyl ether-hexane to give the objectivesubstance.

white powder yield 0.443 g, 78% mp 115-116° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 0.99 (6H, s), 1.64 (2H, d, J=7.2 Hz), 2.29 (2H, s), 2.79 (1H, dd,J=10.4 Hz, 14.6 Hz), 2.98 (1H, dd, J=4.1 Hz, 14.6 Hz), 3.78 (1H, d,J=4.2 Hz), 4.59-4.68 (1H, m), 5.04 (1H, t, J=3.8 Hz), 5.76 (1H, d, J=8.4Hz), 5.89 (1H, tt, J=2.8 Hz, 53.0 Hz), 6.13 (1H, td, J=7.1 Hz, 10.6 Hz),6.34 (1H, d, J=10.5 Hz), 7.01-7.14 (7H, m), 7.17-7.22 (1H, m), 7.30 (1H,t, J=7.8 Hz), 7.42 (2H, dd, J=5.3 Hz, 8.6 Hz); IR (KBr) 3287, 1638,1512, 1227, 1200, 1125 cm⁻¹; Anal. Calcd for C₃₁H₃₀F₅NO₃: C, 66.54; H,5.40; N, 2.50. Found: C, 66.47; H, 5.46; N, 2.49.

Example 289N-[(1RS,2RS)-2-(5-chloro-2-thienyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1) ethyl3-(5-chloro-2-thienyl)-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate

A solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (12.5 g, 60.0 mmol),N-bromosuccinimide (10.7 g, 60.0 mmol) and 2,2′-azobis(isobutyronitrile)(30 mg) in carbon tetrachloride (30 ml) was heated under reflux for 0.5hr. After cooling the reaction solution to room temperature, whiteprecipitate was removed by filtration, and the-precipitate was washedwith diethyl ether. The solvent of the recovered filtrate was evaporatedunder reduced pressure to give a crude product of3-(1,1,2,2-tetrafluoroethoxy)benzyl bromide as a pale-yellow liquid.

To a solution of ethyl 3-(5-chloro-2-thienyl)-3-oxopropionate (11.63 g,49.98 mmol) in 1,2-dimethoxyethane (50 ml) was added a suspension (2.00g, 50.0 mmol) of 60% sodium hydride in liquid paraffin underice-cooling, and the mixture was stirred as it was for 0.5 hr. Asolution of 3-(1,1,2,2-tetrafluoroethoxy)benzyl bromide obtained abovein 1,2-dimethoxyethane (10 ml) was added at room temperature, and themixture was stirred at room temperature for 8 hrs. The reaction solutionwas poured into water and extracted twice with ethyl acetate. Therecovered organic layer was dried over anhydrous magnesium sulfate andthe solvent was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (hexane/ethylacetate=15/1-9/1). Crystallization from hexane gave the objectivesubstance.

white crystal yield 12.58 g, 57% mp 49-51° C.; ¹H-NMR (CDCl₃, 200 MHz) δ1.16 (3H, t, J=7.2 Hz), 3.27 (1H, dd, J=7.5 Hz, 14.1 Hz), 3.36 (1H, dd,J=7.5 Hz, 14.1 Hz), 4.13 (2H, q, J=7.1 Hz), 4.34 (1H, t, J=7.5 Hz), 5.89(1H, tt, J=2.9 Hz, 53.1 Hz), 6.93 (1H, d, J=4.2 Hz), 7.04-7.14 (3H, m),7.23-7.32 (1H, m), 7.53 (1H, d, J=4.0 Hz); IR (KBr) 1725, 1661, 1434,1215, 1148, 1132 cm⁻¹; Anal. Calcd for C₁₈H₁₅ClF₄O₄S: C, 49.27; H, 3.45.Found: C, 49.24; H, 3.20.

2) ethyl(2RS,3RS)-3-(5-chloro-2-thienyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate

While stirring zinc chloride (7.76 g, 57.0 mmol) in diethyl ether (150ml), sodium borohydride (4.31 g, 114 mmol) was added at roomtemperature, and the mixture was stirred at it was for 2 hrs. Theinsoluble material of the mixture was removed by filtration and washedwith diethyl ether to give a solution of zinc borohydride in diethylether. To the obtained solution was added ethyl3-(5-chloro-2-thienyl)-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate(12.50 g, 28.48 mmol) under ice-cooling, and the mixture was stirred atroom temperature for 2 hrs. To the reaction solution was added dilutehydrochloric acid by small portions to decompose excess zincborohydride. The mixture was extracted twice with ethyl acetate. Therecovered organic layer was dried over anhydrous magnesium sulfate, andthe solvent was evaporated under reduced pressure. The obtained crudeproduct was purified by silica gel column chromatography (hexane/ethylacetate=6/1−1/1) to give the objective substance.

colorless liquid yield 12.70 g, 100% ¹H-NMR (CDCl₃, 200 MHz) δ 1.00 (3H,t, J=7.2 Hz), 2.95-3.09 (3H, m), 3.14 (1H, d, J=3.6 Hz), 3.96 (2H, q,J=7.2 Hz), 5.14 (1H, t, J=3.9 Hz), 5.90 (1H, tt, J=2.9 Hz, 53.1 Hz),6.75 (1H, d, J=4.0 Hz), 6.79 (1H, d, J=4.0 Hz), 7.00 (1H, s), 7.06 (2H,d, J=7.8 Hz), 7.28 (1H, t, J=7.9 Hz); IR (neat) 3463, 1725, 1451, 1302,1277, 1198, 1125, 801 cm⁻¹

3)(2RS,3RS)-3-(5-chloro-2-thienyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionicacid

A mixture of ethyl(2RS,3RS)-3-(5-chloro-2-thienyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate(14.27 g, 32.37 mmol), sodium hydroxide (2.39 g, 64.7 mmol), methanol(50 ml) and tetrahydrofuran (50 ml) was stirred at room temperature for6 hrs. The reaction solution was concentrated, diluted with water,acidified with dilute hydrochloric acid, and extracted twice with ethylacetate. The recovered organic layer was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was crystallized from diethyl ether-hexane to give the objectivesubstance.

white crystal yield 9.181 g, 69% mp 105-106° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 3.03-3.11 (3H, m), 5.15-5.17 (1H, m), 5.89 (1H, tt, J=2.9 Hz, 53.1Hz), 6.76 (1H, d, J=3.9 Hz), 6.79 (1H, d, J=3.6 Hz), 7.01 (1H, s), 7.06(2H, d, J=8.7 Hz), 7.27 (1H, t, J=7.8 Hz); IR (KBr) 3358, 3100-2550,1692, 1453, 1287, 1204, 1117, 801 cm⁻¹; Anal. Calcd for C₁₆H₁₃ClF₄O₄S:C, 46.56; H, 3.17. Found: C, 46.59; H, 3.20.

4)(4RS,5RS)-5-(5-chloro-2-thienyl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-(5-chloro-2-thienyl)-3-hydroxy-2-[3-(1,1,2,2tetrafluoroethoxy)benzyl]propionic acid (8.996 g, 21.79 mmol) intetrahydrofuran (80 ml) were added triethylamine (3.65 ml, 26.2 mmol)and diphenylphosphoryl azide (6.60 g, 24.0 mmol), and the mixture washeated under reflux overnight. The solvent of the reaction solution wasevaporated under reduced pressure and the obtained crude product waspurified by silica gel column chromatography (hexane/ethylacetate=3/1-1/1) to give the objective substance.

brown liquid yield 8.480 g, 95% ¹H-NMR (CDCl₃, 200 MHz) δ 2.55 (1H, dd,J=9.8 Hz, 14.0 Hz), 2.66 (1H, dd, J=4.6 Hz, 13.4 Hz), 4.20-4.31 (1H, m),5.19 (1H, br s), 5.86 (1H, d, J=7.6 Hz), 5.91 (1H, tt, J=2.8 Hz, 53.0Hz), 6.87 (2H, s), 6.94 (1H, s), 7.01 (1H, d, J=7.6 Hz), 7.13 (1H, dd,J=1.2 Hz, 8.2 Hz), 7.34 (1H, t, J=7.9 Hz); IR (neat) 3274, 1761, 1451,1196, 1119, 1001 cm⁻¹

5)(1RS,2RS)-2-amino-1-(5-chloro-2-thienyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol

(4RS,5RS)-5-(5-Chloro-2-thienyl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one(8.480 g, 20.69 mmol) and sodium hydroxide (3.31 g, 82.8 mmol) wereheated in ethanol (40 ml)-water (3 ml) under reflux for 4 hrs. Thereaction solution was diluted with brine, and extracted twice with ethylacetate. The recovered organic layer was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel (APS type) column chromatography(hexane/ethyl acetate=3/1-ethyl acetate) to give the objectivesubstance.

yellow liquid yield 7.648 g, 96% ¹H-NMR (CDCl₃, 200 MHz) δ 2.45 (1H, dd,J=9.8 Hz, 13.8 Hz), 2.86 (1H, dd, J=4.1 Hz, 13.5 Hz), 3.27-3.36 (1H, m),4.76 (1H, d, J=4.8 Hz), 5.91 (1H, tt, J=2.7 Hz, 53.1 Hz), 6.78 (1H, d,J=3.6 Hz), 6.83 (1H, d, J=3.6 Hz), 7.06 (2H, d, J=7.4 Hz), 7.12 (1H, d,J=1.6 Hz), 7.32 (1H, t, J=7.8 Hz); IR (neat) 3360-2860, 1586, 1487,1451, 1302, 1279, 1196, 1121, 801 cm⁻¹

6)N-[(1RS,2RS)-2-(5-chloro-2-thienyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2RS)-2-amino-1-(5-chloro-2-thienyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(0.582 g, 1.516 mmol), 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylicacid (0.29 g, 1.52 mmol) and 1-hydroxybenzotriazole hydrate (0.23 g,1.52 mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.29 g,1.52 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white powder yield 0.623 g, 74% mp 177-178° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.95-2.07 (2H, m), 2.16-2.25 (2H, m), 2.68 (2H, t, J=5.9 Hz), 2.80(1H, dd, J=10.4 Hz, 14.6 Hz), 3.06 (1H, dd, J=4.8 Hz, 14.2 Hz), 4.40(1H, d, J=4.2 Hz), 4.62-4.76 (1H, m), 5.15 (1H, t, J=3.6 Hz), 5.81 (1H,d, J=7.6 Hz), 5.90 (1H, tt, J=2.9 Hz, 53.1 Hz), 5.96 (1H, td, J=5.3 Hz,11.6 Hz), 6.27 (1H, d, J=11.8 Hz), 6.83 (2H, s), 7.02-7.21 (6H, m), 7.35(1H, t, J=7.7 Hz); IR (KBr) 3264, 1640, 1537, 1451, 1202, 1117 cm⁻¹;Anal. Calcd for C₂₇H₂₄ClF₄NO₃S: C, 58.54; H, 4.37; N, 2.53. Found: C,58.29; H, 4.36; N, 2.47.

Example 290N-[(1RS,2SR)-2-(4-bromophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1) ethyl 3-(4-bromophenyl)-3-oxopropanoate

To a mixture of 4-bromoacetophenone (80 g, 0.40 mol), ethanol (1 ml) anddiethyl carbonate (350 ml) was added sodium hydride (32 g, 60% in oil)by small portions under ice-cooling and the mixture was stirred at roomtemperature for 4 hrs. The reaction solution was cooled to 0° C. and 6Nhydrochloric acid (200 ml) was added. The mixture was extracted withethyl acetate (200, 100 ml). The extract was washed with water, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was purified by silica gel chromatography (hexane:ethylacetate=10:1-5:1) to give the objective substance (108.9 g,quantitative) as an oil.

IR ν max^(Neat)cm⁻¹: 1742, 1688, 1586, 1424, 1323, 1264, 1200, 1073,1009. ¹H-NMR (CDCl₃) δ: 1.26(3H×3/4, t, J=7.2 Hz), 1.31(3H×1/4, t, J=7.2Hz), 3.96(2H×3/4, s), 4.21(2H×3/4, q, J=7.2 Hz), 4.27(2H×1/4, q, J=7.2Hz), 5.65(1H×1/4, s), 7.50-7.70(2H×5/4, m) 7.75-7.90(2H×3/4, m).

2) ethyl3-(4-bromophenyl)-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate

To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (25 g, 0.12 mol)in ethyl acetate (400 ml) were added N-bromosuccinimide (21.4, 0.12 mol)and 2,2′-azobisisobutyronitrile (0.2 g) and the mixture was heated underreflux for 2.5 hrs. The reaction solution was concentrated under reducedpressure, and diethyl ether and hexane were added. Insoluble materialwas removed, and washed with diethyl ether. The filtrate was evaporatedunder reduced pressure to give3-(1,1,2,2-tetrafluoroethoxy)-1-bromomethylbenzene. To a solution ofethyl 3-(4-bromophenyl)-3-oxopropanoate (27.1 g, 100 mmol) indimethoxyethane (150 ml) was added sodium hydride (4.0 g, 60% in oil,0.1 mol) under ice-cooling and the mixture was stirred for 1 hr. Asolution of 3-(1,1,2,2-tetrafluoroethoxy)-1-bromomethylbenzene obtainedabove in dimethoxyethane (20 ml) was dropwise added and the mixture wasstirred at room temperature for 15 hrs. To the reaction solution wasadded water (300 ml) and the mixture was extracted with ethyl acetate(200 ml×2). The extract was washed with water, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue waspurified by silica gel chromatography (hexane:toluene=1:2-1:5).Crystallization from hexane gave the objective substance (21.1 g, 44%).

mp 48-49° C. IR ν max^(KBr)cm⁻¹: 1721, 1684, 1588, 1277, 1198, 1134,845. Anal. Calcd for C₂₀H₁₇BrF₄O₄ (MW477.24) Calcd: C, 50.33; H, 3.96Found: C, 55.55; H, 3.83 ¹H-NMR (CDCl₃) δ: 1.12 (3H, t, J=7.2 Hz), 3.33(2H, d, J=8.0 Hz), 4.10 (2H, q, J=7.2 Hz), 4.55 (1H, t, J=7.0 Hz), 5.89(1H, tt, J=53.1, 2.2 Hz), 7.00-7.20 (3H, m), 7.20-7.35 (1H, m), 7.42(2H, d, J=8.0 Hz), 7.89 (2H, d, J=8.0 Hz).

3) ethyl(2RS,3RS)-3-(4-bromophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate

To a suspension of anhydride zinc chloride (11.4 g, 83.8 mmol) indiethyl ether (200 ml) was added sodium borohydride (6.34 g, 168 mmol)by small portions, and the mixture was stirred for 2 hrs. The insolublematerial was removed by filtration and washed with diethyl ether. Thefiltrate was ice-cooled, and a solution of ethyl3-(4-bromophenyl)-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate(20 g, 41.9 mmol) in diethyl ether (50 ml) was added. The mixture wasstirred at room temperature for 2 hrs. After cooling again, 2Nhydrochloric acid was added to terminate the reaction. The obtainedmixture was extracted with ethyl acetate (200, 100 ml), washed withwater, dried over anhydrous magnesium sulfate and evaporated underreduced pressure. The residue was purified by silica gel chromatography(hexane:ethyl acetate=5:1-2:1) to give the objective substance (20 g,quantitative) as a colorless oil.

IR ν max^(Neat)cm³¹ ¹: 1715, 1590, 1487, 1302, 1279, 1198, 1123, 1011.¹H-NMR (CDCl₃) δ: 0.95 (3H, t, J=7.2 Hz), 2.90-3.15 (4H, m), 3.90 (2H,d, J=7.2 Hz), 5.02 (1H, br), 5.89 (1H, tt, J=53.1, 2.8 Hz), 6.90-7.15(3H, m), 7.20-7.40 (3H, m), 7.40-7.60 (2H, m).

4)(2RS,3RS)-3-(4-bromophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoicacid

To a solution of ethyl(2RS,3RS)-3-(4-bromophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate(19.5 g, 40.7 mmol) in methanol (100 ml) was added 2N aqueous sodiumhydroxide solution (40.7 ml, 81.4 mmol) and the mixture was stirred atroom temperature for 2.5 hrs. 6N Hydrochloric acid (50 ml) was added toacidify the solution and the mixture was extracted with ethyl acetate(100 ml×2). The extract was washed with water, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The residue wascrystallized from hexane to give the objective substance (16.7 g, 91%).

mp 85-86° C. IR ν max^(KBr)cm⁻¹:1696, 1487, 1279, 1206, 1127. Anal.Calcd for C₁₈H₁₅BrF₄O₄ (MW451.21) Calcd: C, 47.91; H, 3.35 Found: C,47.97; H, 3.33 ¹H-NMR (CDCl₃) δ: 2.85-3.15 (3H, m), 5.06 (1H, d, J=3.8Hz), 5.88 (1H, tt, J=53.1, 2.8 Hz), 6.90-7.15 (3H, m), 7.20-7.40 (2H,m), 7.49 (2H, d, J=8.4 Hz).

5)(4RS,5SR)-5-(4-bromophenyl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-(4-bromophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoicacid (16.2 g, 35.9 mmol) in tetrahydrofuran (150 ml) was addeddiphenylphosphoryl azide (10.0 ml, 46.7 mmol) and triethylamine (7.0 ml,50.3 mmol) was added. The mixture was stirred at room temperature for 1hr and heated under reflux for 2 hrs. The reaction solution wasconcentrated under reduced pressure, and water (100 ml) was added. Themixture was extracted with ethyl acetate (100 ml×2). The extract waswashed with 1N hydrochloric acid and saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate andevaporated under reduced pressure. The residue was purified by silicagel chromatography (hexane:ethyl acetate=3:1-1:1). Hexane was added tothe precipitated crystals and the mixture was filtered to give theobjective substance (14.7 g, 91%).

mp 136-137° C. IR ν max^(KBr)cm⁻¹: 1738, 1489, 1200, 1125, 848. Anal.Calcd for C₁₈H₁₄BrF₄NO₃ (MW448.21) Calcd: C, 48.24; H, 3.15; N, 3.13.Found: C, 48.30; H, 2.87; N, 3.14. ¹H-NMR (CDCl₃) δ: 2.15-2.40 (2H, m),4.20-4.35 (1H, m), 5.03 (1H, brs), 5.77 (1H, d, J=8.0 Hz), 5.90 (1H, tt,J=53.2, 2.7 Hz), 6.87 (1H, s), 6.94 (1H, d, J=7.6 Hz), 7.05-7.15 (1H,m), 7.20-7.40 (3H, m), 7.55-7.65 (2H, m).

6)(1RS,2SR)-2-amino-1-(4-bromophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-1-propanol

To a solution of(4RS,5SR)-5-(4-bromophenyl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one(14.0 g, 31.2 mmol) in ethanol (50 ml) was added 8N aqueous sodiumhydroxide solution (15.6 ml, 125 mmol) and the mixture was heated underreflux for 2 hrs. The reaction solution was concentrated under reducedpressure, and water (200 ml) was added. The mixture was extracted withethyl acetate (200 ml×2). The extract was washed with water, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was crystallized from hexane-diethyl ether to give the objectivesubstance (12.8 g, 97%).

mp 84-86° C. IR ν max^(KBr)cm⁻¹: 3362, 1611, 1588, 1485, 1308, 1196,1119, 1034, 1007. Anal. Calcd for C₁₇H₁₆BrF₄NO₂ (MW422.21) Calcd: C,48.36; H, 3.82; N, 3.32. Found: C, 48.59; H, 3.57; N, 3.37. ¹H-NMR(CDCl₃) δ: 2.36(1H, dd, J=13.4, 10.6 Hz), 2.76(1H, dd, J=13.4, 3.4 Hz),3.20-3.40(1H, m), 4.65(1H, d, J=4.8 Hz), 5.91(1H, tt, J=53.1, 2.8 Hz),6.99(1H, s), 7.06(2H, t, J=6.6 Hz), 7.20-7.40(3H, m), 7.51(2H, d, J=8.6Hz).

7)N-[(1RS,2SR)-2-(4-bromophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-bromophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-1-propanol(5.647 g, 13.37 mmol), 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylicacid (2.52 g, 13.4 mmol) and 1-hydroxybenzotriazole hydrate (2.05 g,13.4 mmol) in acetonitrile (40 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.56 g,13.4 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from ethyl acetate-diisopropyl ether-hexane to give theobjective substance.

white powder yield 7.306 g, 92% mp 184-185° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.95-2.04 (2H, m), 2.16-2.23 (2H, m), 2.66 (2H, t, J=5.9 Hz), 2.77(1H, dd, J=10.7 Hz, 14.6 Hz), 2.97 (1H, dd, J=4.1 Hz, 14.6 Hz), 3.76(1H, d, J=3.9 Hz), 4.61-4.70 (1H, m), 5.02 (1H, t, J=3.9 Hz), 5.75 (1H,d, J=8.4 Hz), 5.89 (1H, tt, J=2.8 Hz, 53.1 Hz), 5.92 (1H, td, J=5.9 Hz,11.4 Hz), 6.20 (1H, d, J=11.7 Hz), 6.96 (1H, dd, J=1.5 Hz, 7.8 Hz), 7.01(1H, s), 7.03-7.17 (4H, m), 7.30 (1H, t, J=7.8 Hz), 7.34 (2H, d, J=8.1Hz), 7.51 (2H, d, J=8.4 Hz); IR (KBr) 3260, 1640, 1532, 1487, 1198, 1125cm⁻¹; Anal. Calcd for C₂₉H₂₆BrF₄NO₃: C, 58.80; H, 4.42; N, 2.36. Found:C, 58.75; H, 4.43; N, 2.35.

Example 291N-[(1RS,2SR)-2-(1,1′-biphenyl-4-yl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

N-[(1RS,2SR)-2-(4-Bromophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.511 g, 0.863 mmol), phenylboronic acid (0.16 g, 1.29 mmol), tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.086 mmol) and sodiumcarbonate (0.18 g, 1.73 mmol) were stirred in toluene (8 ml)-water (8ml) at 90° C. for 1 day. The reaction solution was poured into water,and extracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1). Crystallization fromdiisopropyl ether gave the objective substance.

white powder yield 0.269 g, 53% mp 122-123° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.96-2.05 (2H, m), 2.14-2.24 (2H, m), 2.66 (2H, t, J=5.8 Hz), 2.83(1H, dd, J=10.8 Hz, 14.6 Hz), 3.06 (1H, dd, J=4.5 Hz, 14.7 Hz), 3.60(1H, d, J=3.6 Hz), 4.72-4.82 (1H, m), 5.11 (1H, t, J=3.7 Hz), 5.80 (1H,d, J=8.0 Hz), 5.88 (1H, tt, J=3.0 Hz, 53.1 Hz), 5.91 (1H, td, J=5.4 Hz,11.6 Hz), 6.23 (1H, d, J=11.6 Hz), 6.97-7.17 (6H, m), 7.31-7.64 (10H,m); IR (KBr) 3250, 1634, 1530, 1487, 1285, 1194, 1115, 770, 700 cm⁻¹;Anal. Calcd for C₃₅H₃₁F₄NO₃.0.1H₂O.0.5i-Pr₂O: C, 71.04; H, 5.99; N,2.18. Found: C, 70.75; H, 5.99; N, 2.23.

Example 292N-[(1RS,2SR)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-2-[4-(3-thienyl)phenyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

N-[(1RS,2SR)-2-(4-Bromophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.519 g, 0.876 mmol), thiophene-3-boronic acid (0.17 g, 1.31 mmol),tetrakis (triphenylphosphine)palladium(0) (0.10 g, 0.088 mmol) andsodium carbonate (0.19 g, 1.75 mmol) were stirred in toluene (8ml)-water (8 ml) at 90° C. for 1 day. The reaction solution was pouredinto water, and extracted twice with ethyl acetate. The recoveredorganic layer was dried over anhydrous sodium sulfate and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=3/1-1/1).Crystallization from ethyl acetate-diisopropyl ether-hexane gave theobjective substance.

pale-brown powder yield 0.334 g, 64% mp 178-179° C.; ¹H-NMR (CDCl₃, 200MHz) δ 1.92-2.04 (2H, m), 2.14-2.23 (2H, m), 2.66 (2H, t, J=5.9 Hz),2.81 (1H, dd, J=10.5 Hz, 14.7 Hz), 3.03 (1H, dd, J=4.6 Hz, 14.4 Hz),3.63 (1H, d, J=3.6 Hz), 4.67-4.81 (1H, m), 5.07 (1H, t, J=3.7 Hz), 5.80(1H, d, J=8.4 Hz), 5.88 (1H, tt, J=2.9 Hz, 53.1 Hz), 5.90 (1H, td, J=5.0Hz, 12.2 Hz), 6.22 (1H, d, J=11.8 Hz), 6.95-7.17 (6H, m), 7.26-7.50 (6H,m), 7.62 (2H, d, J=8.2 Hz); IR (KBr) 3283, 2936, 1640, 1532, 1200, 1123,783 cm⁻¹; Anal. Calcd for C₃₃H₂₉F₄NO₃S: C, 66.54; H, 4.91; N, 2.35.Found: C, 66.37; H, 4.86; N, 2.28.

Example 293N-[(1RS,2SR)-2-(2′-chloro[1,1′-biphenyl]-4-yl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

N-[(1RS,2SR)-2-(4-Bromophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.529 g, 0.893 mmol), 2-chlorophenylboronic acid (0.42 g, 2.68 mmol),tetrakis (triphenylphosphine)palladium(0) (0.20 g, 0.18 mmol) and sodiumcarbonate (0.38 g, 3.58 mmol) were stirred in toluene (8 ml)-water (8ml) at 90° C. for 2 days. The reaction solution was poured into water,and extracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1). Crystallization fromdiisopropyl ether-hexane gave the objective substance.

white powder yield 0.203 g, 36% mp 172-173° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.95-2.04 (2H, m), 2.16-2.22 (2H, m), 2.66 (2H, t, J=5.9 Hz), 2.86,(1H, dd, J=10.8 Hz, 14.4 Hz), 3.07 (1H, dd, J=4.5 Hz, 14.7. Hz), 3.62(1H, d, J=3.9 Hz), 4.72-4.81 (1H, m), 5.11 (1H, t, J=3.9 Hz), 5.83 (1H,d, J=8.4 Hz), 5.89 (1H, tt, J=2.9 Hz, 53.0 Hz), 5.93 (1H, td, J=5.7 Hz,11.6 Hz), 6.25 (1H, d, J=11.7 Hz), 6.96-7.16 (6H, m), 7.26-7.36 (4H, m),7.46-7.54 (5H, m); IR (KBr) 3753, 3233, 3061, 1640, 1306, 1198, 1123,1030, 762 cm⁻¹; Anal. Calcd for C₃₅H₃₀ClF₄NO₃: C, 67.36; H, 4.85; N,2.24. Found: C, 66.99; H, 5.05; N, 2.08.

Example 294N-[(1RS,2SR)-2-(4′-chloro[1,1′-biphenyl]-4-yl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

N-[(1RS,2SR)-2-(4-Bromophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.500 g, 0.844 mmol), 4-chlorophenylboronic acid (0.26 g, 1.69 mmol),tetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) and sodiumcarbonate (0.27 g, 2.53 mmol) were stirred in toluene (10 ml)-water (10ml) at 90° C. for 2 days. The reaction solution was poured into water,and extracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1). Crystallization fromdiisopropyl ether-hexane gave the objective substance.

pale-brown crystal yield 0.136 g, 26% mp 167-168° C.; ¹H-NMR (CDCl₃, 300MHz) δ 1.95-2.03 (2H, m), 2.15-2.22 (2H, m), 2.66 (2H, t, J=5.9 Hz),2.83 (1H, dd, J=10.7 Hz, 14.6 Hz), 3.04 (1H, dd, J=4.1 Hz, 14.9 Hz),3.63 (1H, d, J=3.6 Hz), 4.71-4.79 (1H, m), 5.11 (1H, t, J=3.8 Hz), 5.80(1H, d, J=8.4 Hz), 5.88 (1H, tt, J=2.9 Hz, 53.1 Hz), 5.90 (1H, td, J=5.7Hz, 11.4 Hz), 6.23 (1H, d, J=12.0 Hz), 6.96-7.16 (6H, m), 7.30 (1H, t,J=8.0 Hz), 7.41 (2H, d, J=8.7 Hz), 7.50-7.59 (6H, m); IR (KBr) 3289,2932, 1638, 1530, 1487, 1204, 1123, 1096, 818 cm⁻¹; Anal. Calcd forC₃₅H₃₀ClF₄NO₃: C, 67.36; H, 4.85; N, 2.24. Found: C, 67.37; H, 4.87; N,2.15.

Example 295N-[(1RS,2SR)-2-(3′-chloro[1,1′-biphenyl]-4-yl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

N-[(1RS,2SR)-2-(4-Bromophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.500 g, 0.844 mmol), 3-chlorophenylboronic acid (0.26 g, 1.69 mmol),tetrakis (triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) and sodiumcarbonate (0.27 g, 2.53 mmol) were stirred in toluene (10 ml)-water (10ml) at 90° C. for 2 days. The reaction solution was poured into water,and extracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1). Crystallization fromdiisbpropyl ether-hexane gave the objective substance.

pale-brown crystal yield 0.165 g, 31% mp 131-132° C.; ¹H-NMR (CDCl₃, 300MHz) δ 1.95-2.03 (2H, m), 2.16-2.22 (2H, m), 2.67 (2H, t, J=5.9 Hz),2.83 (1H, dd, J=10.5 Hz, 14.4 Hz), 3.03 (1H, dd, J=4.2 Hz, 14.7 Hz),3.66 (1H, d, J=3.9 Hz), 4.70-4.79 (1H, m), 5.11 (1H, t, J=3.8 Hz), 5.80,(1H, d, J=8.1 Hz), 5.88 (1H, tt, J=2.9 Hz, 53.0 Hz), 5.91. (1H, td,J=5.7 Hz, 11.4 Hz), 6.23 (1H, d, J=11.7 Hz), 6.98-7.17 (6H, m),7.28-7.43 (3H, m), 7.46-7.60 (6H, m); IR (KBr) 3270, 2938, 1640, 1514,1200, 1125, 783 cm⁻¹; Anal. Calcd for C₃₅H₃₀ClF₄NO₃: C, 67.36; H, 4.85;N, 2.24. Found: C, 67.42; H, 4.80; N, 2.10.

Example 296N-[(1RS,2SR)-2-hydroxy-2-(2′-methoxy[1,1′-biphenyl]-4-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

N-[(1RS,2SR)-2-(4-Bromophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.530 g, 0.895 mmol), 2-methoxyphenylboronic acid (0.20 g, 1.34 mmol),tetrakis (triphenylphosphine)palladium(0) (0.10 g, 0.089 mmol) andsodium carbonate (0.19 g, 1.79 mmol) were stirred in toluene (8ml)-water (8 ml) at 90° C. for 1 day. The reaction solution was pouredinto water, and extracted twice with ethyl acetate. The recoveredorganic layer was dried over anhydrous sodium sulfate and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane/ethyl acetate=3/1-1/1).Crystallization from ethyl acetate-diisopropyl ether-hexane gave theobjective substance.

white powder yield 0.307 g, 55% mp 148-150° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.95-2.05 (2H, m), 2.16-2.22 (2H, m), 2.66 (2H, t, J=5.7 Hz), 2.85(1H, dd, J=10.7 Hz, 14.9 Hz), 3.08 (1H, dd, J=4.2 Hz, 14.7 Hz), 3.48(1H, d, J=3.9 Hz), 3.82 (3H, s), 4.74-4.82 (1H, m), 5.09 (1H, t, J=3.6Hz), 5.79 (1H, d, J=8.7 Hz), 5.89 (1H, tt, J=2.9 Hz, 53.1 Hz), 5.91 (1H,td, J=5.5 Hz, 11.2 Hz), 6.24 (1H, d, J=11.7 Hz), 6.97-7.18 (8H, m),7.28-7.36 (3H, m), 7.49 (2H, d, J=8.1 Hz), 7.57 (2H, d, J=8.1 Hz); IR(KBr) 3264, 2938, 1638, 1528, 1487, 1275, 1190, 1117, 762 cm⁻¹; Anal.Calcd for C₃₆H₃₃F₄NO₄.0.2H₂O: C, 69.38; H, 5.40; N, 2.25. Found: C,69.11; H, 5.33; N, 2.05.

Example 297N-[(1RS,2SR)-2-hydroxy-2-(4′-methoxy[1,1′-biphenyl]-4-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

N-[(1RS,2SR)-2-(4-Bromophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.500 g, 0.844 mmol), 4-methoxyphenylboronic acid (0.26 g, 1.69 mmol),tetrakis (triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) and sodiumcarbonate (0.27 g, 2.53 mmol) were stirred in toluene (10 ml)-water (10ml) at 90° C. for 1 day. The reaction solution was poured into water,and extracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1). Crystallization fromdiisopropyl ether-hexane gave the objective substance.

white crystal yield 0.310 g, 59% mp 162-163° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.94-2.03 (2H, m), 2.15-2.22 (2H, m), 2.66 (2H, t, J=5.9 Hz), 2.83(1H, dd, J=10.7 Hz, 14.6 Hz), 3.05 (1H, dd, J=4.2 Hz, 14.7 Hz), 3.54(1H, d, J=3.6 Hz), 3.86 (3H, s), 4.73-4.81 (1H, m), 5.09 (1H, t, J=3.9Hz), 5.78 (1H, d, J=8.7 Hz), 5.88 (1H, tt, J=2.9 Hz, 53.1 Hz), 5.90 (1H,td, J=5.7 Hz, 11.4 Hz), 6.23 (1H, d, J=11.7 Hz), 6.96-7.16 (8H, m), 7.30(1H, t, J=8.0 Hz), 7.49-7.59 (6H, m); IR (KBr) 3299, 2930, 1638, 1530,1503, 1277, 1229, 1198, 1125, 820 cm⁻¹; Anal. Calcd for C₃₆H₃₃F₄NO₄: C,69.78; H, 5.37; N, 2.26. Found: C, 69.69; H, 5.17; N, 2.10.

Example 298N-[(1RS,2SR)-2-hydroxy-2-(3′-methoxy[1,1′-biphenyl]-4-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

N-[(1RS,2SR)-2-(4-Bromophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.500 g, 0.844 mmol), 3-methoxyphenylboronic acid (0.26 g, 1.69 mmol),tetrakis (triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) and sodiumcarbonate (0.27 g, 2.53 mmol) were stirred in toluene (10 ml)-water (10ml) at 90° C. for 1 day. The reaction solution was poured into water,and extracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1). Crystallization fromdiisopropyl ether-hexane gave the objective substance.

white crystal yield 0.241 g, 46% mp 79-81° C.; ¹H-NMR (CDCl₃, 300 MHz) δ1.95-2.03 (2H, m), 2.16-2.22 (2H, m), 2.66 (2H, t, J=5.7 Hz), 2.83 (1H,dd, J=10.5 Hz, 14.7 Hz), 3.05 (1H, dd, J=4.1 Hz, 14.6 Hz), 3.60 (1H, d,J=3.9 Hz), 3.87 (3H, s), 4.73-4.80 (1H, m), 5.10 (1H, t, J=3.8 Hz), 5.79(1H, d, J=8.4 Hz), 5.88 (1H, tt, J=2.9 Hz, 53.0 Hz), 5.91 (1H, td, J=5.7Hz, 11.4 Hz), 6.23 (1H, d, J=11.7 Hz), 6.91 (1H, dd, J=2.1 Hz, 7.8 Hz),6.99 (1H, dd, J=1.5 Hz, 7.5 Hz), 7.03-7.20 (7H, m), 7.30 (1H, t, J=7.8Hz), 7.37 (1H, t, J=8.0 Hz), 7.52 (2H, d, J=8.1 Hz), 7.61 (2H, d, J=8.1Hz); IR (KBr) 3268, 2932, 1638, 1518, 1483, 1298, 1277, 1194, 1121, 779cm⁻¹; Anal. Calcd for C₃₆H₃₃F₄NO₄: C, 69.78; H, 5.37; N, 2.26. Found: C,69.76; H, 5.70; N, 2.07.

Example 299N-[(1RS,2SR)-2-(4′-formyl[1,1′-biphenyl]-4-yl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

N-[(1RS,2SR)-2-(4-Bromophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.822 g, 1.388 mmol), 4-formylphenylboronic acid (0.31 g, 2.08 mmol),tetrakis (triphenylphosphine)palladium(0) (0.16 g, 0.14 mmol) and sodiumcarbonate (0.29 g, 2.78 mmol) were stirred in toluene (10 ml)-water (10ml) at 90° C. for 1 day. The reaction solution was poured into water,and extracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous sodium. sulfate and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1). Crystallization fromdiisopropyl ether-hexane gave the objective substance.

white powder yield 0.214 g, 25% mp 174-176° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.97-2.04 (2H, m), 2.16-2.22. (2H, m), 2.67 (2H, t, J=5.9 Hz), 2.85(1H, dd, J=10.5 Hz, 14.7 Hz), 3.04 (1H, dd, J=3.8 Hz, 14.3 Hz), 3.69(1H, d, J=3.9 Hz), 4.72-4.80 (1H, m), 5.14 (1H, t, J=3.5 Hz), 5.81 (1H,d, J=8.4 Hz), 5.88 (1H, tt, J=2.6 Hz, 53.0 Hz), 5.91 (1H, td, J=5.6 Hz,11.4 Hz), 6.24 (1H, d, J=11.7 Hz), 6.98-7.17 (6H, m), 7.31 (1H, t, J=7.8Hz), 7.58 (2H, d, J=8.1 Hz), 7.67 (2H, d, J=8.4 Hz), 7.77 (2H, d, J=8.1Hz), 7.97 (2H, d, J=8.1 Hz), 10.06 (1H, s); IR (KBr) 3324, 2940, 1701,1626, 1605, 1532, 1308, 1275, 1200, 1119, 806, 774 cm⁻¹; Anal. Calcd forC₃₆H₃₁F₄NO₄: C, 70.01; H, 5.06; N, 2.27. Found: C, 69.89; H, 5.19; N,2.01.

Example 300N-[(1RS,2SR)-2-(3′-formyl[1,1′-biphenyl]-4-yl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

N-[(1RS,2SR)-2-(4-Bromophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethbxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.812 g, 1.371 mmol), 3-formylphenylboronic acid (0.41 g, 2.74 mmol),tetrakis (triphenylphosphine)palladium(0) (0.32 g, 0.27 mmol) and sodiumcarbonate. (0.44 g, 4.11 mmol) were stirred in toluene. (10 ml)-water(10 ml) at 90° C. for 1 day. The reaction solution was poured intowater, and extracted twice with ethyl acetate. The recovered organiclayer was dried over anhydrous sodium sulfate and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate=3/1-1/1).Crystallization from diisopropyl ether-hexane gave the objectivesubstance.

pale-brown powder yield 0.285 g, 34% mp 103-105° C.; ¹H-NMR (CDCl₃, 300MHz) δ 1.95-2.04 (2H, m), 2.16-2.22 (2H, m), 2.67 (2H, t, J=5.9. Hz),2.84 (1H, dd, J=10.8 Hz, 14.7 Hz), 3.05 (1H, dd, J=4.2 Hz, 14.4 Hz),3.67 (1H, d, J=3.9 Hz), 4.71-4.80 (1H, m), 5.14 (1H, t, J=3.9 Hz), 5.81(1H, d, J=8.4 Hz), 5.89 (1H, tt, J=2.8 Hz, 53.0 Hz), 5.91 (1H, td, J=5.4Hz, 12.9 Hz), 6.25 (1H, d, J=12.0 Hz), 6.98-7.17 (6H, m), 7.31 (1H, t,J=8.0 Hz), 7.57-7.67 (5H, m), 7.88 (2H, dd, J=2.1 Hz, 7.2 Hz), 8.12 (1H,s), 10.10 (1H, s); IR (KBr) 3264, 2938, 1701, 1640, 1518, 1449, 1304,1279, 1198, 1123, 793 cm⁻¹; Anal. Calcd for C₃₆H₃₁F₄NO₄: C, 70.01; H,5.06; N, 2.27. Found: C, 70.08; H, 5.19; N, 2.16.

Example 301N-[(1RS,2SR)-2-(2′-formyl[1,1′-biphenyl]-4-yl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

N-[(1RS,2SR)-2-(4-Bromophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.812 g, 1.371 mmol), 2-formylphenylboronic acid (0.41 g, 2.74 mmol),tetrakis (triphenylphosphine)palladium(0) (0.32 g, 0.27 mmol) and sodiumcarbonate (0.44 g, 4.11 mmol) were stirred in toluene (10 ml)-water (10ml) at 90° C. for 1 day. The reaction solution was poured into water,and extracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1). Crystallization fromdiisopropyl ether-hexane gave the objective substance.

pale-brown crystal yield 0.423 g, 50% mp 195-196° C.; ¹H-NMR (CDCl₃, 300MHz) δ 1.96-2.04 (2H, m), 2.16-2.22 (2H, m), 2.67 (2H, t, J=5.9 Hz),2.86 (1H, dd, J=10.5 Hz, 14.7 Hz), 3.06 (1H, dd, J=4.4 Hz, 14.6 Hz),3.77 (1H, d, J=3.9 Hz), 4.72-4.81 (1H, m), 5.16 (1H, t, J=3.6 Hz), 5.85(1H, d, J=8.4 Hz), 5.90 (1H, tt, J=2.7 Hz, 53.0 Hz), 5.93 (1H, td, J=5.7Hz, 11.4 Hz), 6.26 (1H, d, J=11.7 Hz), 6.98-7.18 (6H, m), 7.32 (1H, t,J=7.8 Hz), 7.40-7.68 (7H, m), 8.04 (1H, d, J=8.1 Hz), 9.99 (1H, s); IR(KBr) 3227, 2930, 1688, 1636, 1304, 1198, 1123, 770 cm⁻¹; Anal. Calcdfor C₃₆H₃₁F₄NO₄: C, 70.01; H, 5.06; N, 2.27. Found: C, 70.00; H, 5.13;N, 2.20.

Example 302N-[(1RS,2SR)-2-[2′-(hydroxymethyl)[1,1′-biphenyl]-4-yl]-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution ofN-[(1RS,2SR)-2-(2′-formyl[1,1′-biphenyl]-4-yl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(168 mg, 0.272 mmol) in methanol (3 ml) was added sodium borohydride (10mg, 0.27 mmol) at room temperature and the mixture was stirred as it wasfor 0.5 hr. To the reaction solution was added aqueous ammonium chloridesolution, and the mixture was stirred as it was for 1 hr. The recoveredprecipitate was washed with water and diisopropyl ether-hexane to givethe objective substance.

white powder yield 137 mg, 81% mp 152-154° C.; ¹H-NMR (CDCl₃, 300 MHz) δ1.60 (1H, t, J=5.7 Hz), 1.95-2.04 (2H, m), 2.16-2.22 (2H, m), 2.64-2.69(2H, m), 2.86 (1H, dd, J=10.7 Hz, 14.9 Hz), 3.08 (1H, dd, J=4.1 Hz, 14.6Hz), 3.62 (1H, d, J=3.0 Hz), 4.62 (2H, d, J=5.4 Hz), 4.72-4.80 (1H, m),5.11 (1H, t, J=3.8 Hz), 5.82 (1H, d, J=8.7 Hz), 5.90 (1H, tt, J=2.7 Hz,53.0 Hz), 5.93 (1H, td, J=5.8 Hz, 11.6 Hz), 6.25 (1H, d, J=11.7 Hz),6.98 (1H, dd, J=1.5 Hz, 7.5 Hz), 7.04-7.17 (5H, m), 7.27-7.43 (6H, m),7.51-7.58 (3H, m); IR (KBr) 3289, 1638, 1526, 1200, 1125, 1036, 762cm⁻¹; Anal. Calcd for C₃₆H₃₃F₄NO₄: C, 69.78; H, 5.37; N, 2.26. Found: C,69.47; H, 5.39; N, 2.16.

Example 303N-[(1RS,2SR)-2-[3′-(hydroxymethyl)[1,1′-biphenyl]-4-yl]-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution ofN-[(1RS,2SR)-2-(3′-formyl[1,1′-biphenyl]-4-yl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(123 mg, 0.199 mmol) in methanol (3 ml) was added sodium borohydride (8mg, 0.20 mmol) at room temperature and the mixture was stirred as it wasfor 0.5 hr. To the reaction solution was added aqueous ammonium chloridesolution, and the mixture was stirred as it was for 1 hr. The recoveredprecipitate was washed with water and diisopropyl ether-hexane to givethe objective substance.

white powder yield 101 mg, 82% mp 178-179° C.; ¹H-NMR (CDCl₃, 300 MHz) δ1.74 (1H, t, J=5.3 Hz), 1.95-2.03 (2H, m), 2.16-2.22 (2H, m), 2.66 (2H,t, J=5.9 Hz), 2.83 (1H, dd, J=10.4 Hz, 14.6 Hz), 3.05 (1H, dd, J=4.2 Hz,14.4 Hz), 3.60 (1H, d, J=3.9 Hz), 4.72-4.80 (1H, m), 4.78 (2H, d, J=4.2Hz), 5.11 (1H, t, J=3.6 Hz), 5.79 (1H, d, J=8.4 Hz), 5.88 (1H, tt, J=3.2Hz, 53.0 Hz), 5.91 (1H, td, J=5.9 Hz, 11.7 Hz), 6.24 (1H, d, J=12.0 Hz),6.98-7.16 (6H, m), 7.26-7.64 (9H, m); IR (KBr) 3268, 1638, 1532, 1198,1127, 787 cm⁻¹; Anal. Calcd for C₃₆H₃₃F₄NO₄: C, 69.78; H, 5.37; N, 2.26.Found: C, 69.47; H, 5.22; N, 2.15.

Example 304N-[(1RS,2SR)-2-[4′-(hydroxymethyl)[1,1′-biphenyl]-4-yl]-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution ofN-[(1RS,2SR)-2-(4′-formyl[1,1′-biphenyl]-4-yl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(107 mg, 0.173 mmol) in methanol (3 ml) was added sodium borohydride (7mg, 0.17 mmol) at room temperature and the mixture was stirred as it wasfor 0.5 hr. To the reaction solution was added aqueous ammonium chloridesolution, and the mixture was stirred as it was for 1 hr. The recoveredprecipitate was washed with water and diisopropyl ether-hexane to givethe objective substance.

white powder yield 85 mg, 80% mp 189-191° C.; ¹H-NMR (CDCl₃-DMSO-d₆, 300MHz) δ 1.95-2.01 (2H, m), 2.14-2.24 (2H, m), 2.67 (2H, t, J=5.6 Hz),2.89 (1H, dd, J=11.0 Hz, 14.3 Hz), 2.98 (1H, dd, J=4.1 Hz, 14.6 Hz),3.69 (1H, br s), 4.72 (2H, d, J=5.1 Hz), 4.72-4.81 (1H, m), 4.87 (1H, d,J=2.7 Hz), 5.06 (1H, t, J=3.5 Hz), 5.87 (1H, td, J=5.7 Hz, 11.6 Hz),5.92 (1H, tt, J=2.9 Hz, 53.1 Hz), 6.20 (1H, d, J=12.3 Hz), 6.69 (1H, d,J=8.7 Hz), 6.96 (1H, d, J=7.5 Hz), 7.02-7.16 (5H, m), 7.27 (1H, t, J=7.8Hz), 7.46 (2H, d, J=7.8 Hz), 7.56-7.63 (6H, m); IR (KBr) 3268, 1636,1520, 1206, 1119 cm⁻¹; Anal. Calcd for C₃₆H₃₃F₄NO₄: C, 69.78; H, 5.37;N, 2.26. Found: C, 69.53; H, 5.24; N, 2.14.

Example 305N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-5,5-dimethyl-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1) 3-methyl-3-phenylbutanoic acid

While stirring powdery magnesium (9.56 g, 393 mmol) and iodine (onecrumb) in tetrahydrofuran (10 ml), a solution of1-chloro-2-methyl-2-phenylpropane (26.53 g, 157.3 mmol) and1,2-dibromoethane (29.6 g, 157 mmol) in tetrahydrofuran (100 ml) wasdropwise added at a rate permitting the reaction solution to gentlyreflux. After completion of the dropwise addition, the mixture wasstirred at 60° C. for 4 hrs. The reaction solution was cooled to −78°C., and pulverized dry ice (50 g) was carefully added. After completionof the dropwise addition, the reaction solution was gradually warmed toroom temperature with stirring. The reaction solution was diluted withwater, acidified with conc. hydrochloric acid, and extracted twice withethyl acetate. The solvent of the recovered organic layer was evaporatedunder reduced pressure. The obtained residue was mixed with sodiumhydroxide (6 g) and water (200 ml). The obtained aqueous solution waswashed with diethyl ether-hexane, acidified with conc. hydrochloricacid, and extracted twice with ethyl acetate. The recovered organiclayer was dried over anhydrous magnesium sulfate and the solvent wasevaporated under reduced pressure to give the objective substance.

yellow liquid yield 20.83 g, 74% ¹H-NMR (CDCl₃, 200 MHz) δ 1.47 (6H, s),2.65 (2H, s), 7.17-7.40 (5H, m), 10.48 (1H, br s); IR (neat) 2967, 1699,1634, 1260, 1167, 772, 700 cm⁻¹

2) 3-methyl-3-phenyl-1-butanol

To a suspension of lithium aluminum hydride (8.62 g, 228 mmol) intetrahydrofuran (200 ml) was added dropwise a solution of3-methyl-3-phenylbutanoic acid (20.26 g, 113.7 mmol) in tetrahydrofuran(100 ml) under ice-cooling, and the mixture was stirred overnight atroom temperature. After ice-cooling the reaction solution, water (8 ml),15% aqueous sodium hydroxide solution (8 ml) and water (20 ml) weresuccessively added dropwise to decompose excess lithium aluminumhydride. The mixture was stirred as it was at room temperature for 2hrs. The resulting precipitate was removed by filtration, and theprecipitate was washed with ethyl acetate. The solvent of the recoveredfiltrate was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (hexane/ethyl acetate=1/1)to give the objective substance.

colorless liquid yield 18.09 g, 97% ¹H-NMR (CDCl₃, 200 MHz) δ 1.00 (1H,t, J=5.3 Hz), 1.35 (6H, s), 1.95 (2H, t, J=7.4 Hz), 3.44-3.54 (2H, m),7.14-7.40 (5H, m); IR (neat) 3333, 2965, 1497, 1445, 1057, 1022, 764,700 cm⁻¹

3) 5,5-dimethyl-5-phenyl-2-pentanoic acid

To a solution of 3-methyl-3-phenyl-1-butanol (18.09 g, 110.1 mmol) andtriethylamine (23.0 ml, 165 mmol) in ethyl acetate (150 ml) was dropwiseadded a solution of methanesulfonyl chloride (15.1 g, 132 mmol) in ethylacetate (30 ml) under ice-cooling, and the mixture was stirred as it wasfor 15 min. The resulting precipitate (triethylamine hydrochloride) wasremoved by filtration, and the precipitate was washed with ethylacetate. The recovered ethyl acetate solution was concentrated underreduced pressure to give a crude product of mesylate as a yellow liquid.

To a solution of diethyl malonate (22.8 g, 132 mmol) in tetrahydrofuran(100 ml) was gradually added a suspension (5.29 g, 132 mmol) of 60%sodium hydride in paraffin under ice-cooling, and the mixture wasstirred as it was for 0.5 hr. A solution of the liquid obtained above intetrahydrofuran (50 ml) was dropwise added thereto at room temperature,and the mixture was stirred at 60° C. overnight. Water was added to thereaction solution, and the mixture was stirred and extracted twice withethyl acetate. The recovered organic layer was dried over anhydrousmagnesium sulfate and the solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel column chromatography(hexane/ethyl acetate=15/1-6/1) to give diethyl(3-methyl-3-phenylbutyl)malonate (31.8 g) as a colorless liquid.

The obtained liquid and conc. hydrochloric acid (50 ml) in acetic. acid(100 ml) were stirred at 100° C. overnight. The reaction solution wasevaporated under reduced pressure and the obtained residue was stirredat 175° C. for 4 hrs. to give the objective substance.

yellow liquid yield 18.86 g, 83% ¹H-NMR (CDCl₃, 200 MHz) 1.21-1.47 (2H,m), 1.31 (6H, s), 1.63-1.69 (2H, m), 2.25 (2H, t, J=7.3 Hz), 7.14-7.23(1H, m), 7.29-7.35 (4H, m); IR (neat) 2963, 1709, 1279, 766, 700 cm⁻¹

4) 9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one

To a solution of 5,5-dimethyl-5-phenyl-2-pentanoic acid (18.86 g, 91.43mmol) and N,N-dimethylformamide (2 drops) in tetrahydrofuran (100 ml)was dropwise added oxalyl chloride (12.0 ml, 137 mmol) at roomtemperature and the mixture was stirred as it was for 0.5 hr. Thesolvent of the reaction mixture was evaporated under reduced pressure togive acid chloride as a yellow liquid.

While stirring a suspension of aluminum chloride (24.4 g, 183 mmol) inmethylene chloride (100 ml), a solution of acid chloride obtained abovein methylene chloride (400 ml) was dropwise added for 2 days. Whileice-cooling the reaction solution, water was added to terminate thereaction. The methylene chloride layer of the mixture was separated, andthe aqueous layer was extracted with diethyl ether. The recoveredorganic layer was dried over anhydrous magnesium sulfate and the solventwas-evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=15/1-6/1) togive the objective substance.

yellow liquid yield 5.780 g, 34% ¹H-NMR (CDCl₃, 200 MHz) δ 1.36 (6H, s),1.83-2.02 (4H, m), 2.75 (2H, t, J=6.8 Hz), 7.21-7.29 (1H, m), 7.36-7.43(3H, m); IR (neat) 2965, 1684, 1597, 1456, 1250, 764 cm⁻¹

5) 9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol

To a solution of9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one (5.780 g,30.70 mmol) in methanol (40 ml) was added sodium borohydride (1.16 g,30.7 mmol) by small portions under ice-cooling, and the mixture wasstirred overnight at room temperature. The reaction solution wasconcentrated under reduced pressure, diluted with water, and extractedtwice with ethyl acetate. The recovered organic layer was dried overanhydrous magnesium sulfate and the solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate=9/1-6/1) to give the objectivesubstance.

yellow liquid yield 5.245 g, 90% ¹H-NMR (CDCl₃, 300 MHz) δ 1.33 (3H, s),1.45 (3H, s), 1.61-1.94 (5H, m), 1.76 (1H, d, J=4.5 Hz), 2.01-2.10 (1H,m), 5.15-5.20 (1H, m), 7.19-7.25 (2H, m), 7.39-7.44 (1H, m), 7.58-7.62(1H, m); IR (neat) 3335, 2926, 1476, 1443, 1362, 1030, 760 cm⁻¹

6) 4-bromo-9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol

To a solution of9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol (5.128 g,26.95 mmol) and N,N,N′,N′-tetramethylethylenediamine (6.89 g, 59.3 mmol)in hexane (100 ml) was dropwise added a solution (37.1 ml, 59.3 mmol) of1.6 M n-butyllithium in hexane under ice-cooling, and the mixture wasstirred at 35° C. overnight. After the reaction mixture was cooled to−78° C., 1,2-dibromotetrafluoroethane (14.0 g, 53.9 mmol) was added. Themixture was warmed to room temperature with stirring, and stirred atroom temperature for 2 hrs. The reaction solution was poured into water,and extracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The obtained crude product was purified bysilica gel column chromatography (hexane/ethyl acetate=15/1) to give theobjective substance.

yellow solid yield 4.614 g, 64% Recrystallization from hexane gave whitecrystals. mp 91-92° C.; ¹H-NMR (CDCl₃, 300 MHz) δ 1.38 (3H, s), 1.40(3H, s), 1.54-1.62 (1H, m), 1.71-1.88 (2H, m), 2.05-2.36 (3H, m), 2.22(1H, d, J=4.8 Hz), 5.56-5.59 (1H, m), 7.05 (1H, t, J=8.0 Hz), 7.42-7.45(2H, m); IR (KBr) 3354, 2955, 1447, 945, 918, 775, 747 cm⁻¹; Anal. Calcdfor C₁₃H₁₇BrO: C, 58.01; H, 6.37. Found: C, 58.34; H, 6.51.

7) 1-bromo-5,5-dimethyl-6,7-dihydro-5H-benzo[a]cycloheptene

A solution of4-bromo-9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol(4.402 g, 16.35 mmol) and p-toluenesulfonic acid monohydrate (0.31 g,1.64 mmol) in toluene (80 ml) was heated under reflux in a reactionvessel equipped with a Dean-Stark trap under dehydrating conditions for0.5 hr. After the reaction solution was cooled to room temperature, thesolvent was evaporated under reduced pressure. The obtained crudeproduct was purified by silica gel column chromatography (hexane) togive the objective substance.

colorless liquid yield 3.887 g, 95% ¹H-NMR (CDCl₃, 200 MHz) δ 1.34 (6H,s), 1.83 (2H, t, J=6.8 Hz), 2.42-2.52 (2H, m), 6.05 (1H, td, J=4.4 Hz,12.5 Hz), 6.91 (1H, td, J=1.9 Hz), 6.98 (1H, t, J=8.0 Hz), 7.33 (1H, d,J=7.8 Hz), 7.49 (1H, dd, J=1.3 Hz, 7.9 Hz); IR (neat) 2965, 2919, 1454,1420, 1404, 885, 766 cm⁻¹

8) 5,5-dimethyl-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid

To a solution of1-bromo-5,5-dimethyl-6,7-dihydro-5H-benzo[a]cycloheptene (3.879 g, 15.44mmol) in diethyl ether (30 ml) was dropwise added a solution (11.6 ml,18.5 mmol) of 1.6 M n-butyllithium in hexane at −78° C., and the mixturewas stirred at room temperature for 4 hrs. After the reaction mixturewas cooled to −78° C., pulverized dry ice (5 g) was added, and themixture was warmed to room temperature with stirring. The reactionsolution was diluted with water and washed with diethyl ether. Themixture was acidified with 1N hydrochloric acid, and extracted twicewith ethyl acetate. The recovered organic layer was dried over anhydrousmagnesium sulfate and the solvent was evaporated under reduced pressure.The obtained crude crystals were washed with hexane to give theobjective substance.

white crystal yield 1.540 g, 46% mp 165-166° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.37 (6H, s), 1.89 (2H, t, J=6.6 Hz), 2.44-2.54 (2H, m), 6.08 (1H, td,J=4.4 Hz, 12.4 Hz), 6.92 (1H, td, J=2.0 Hz, 12.3 Hz), 7.22 (1H, t, J=7.9Hz), 7.57 (1H, dd, J=1.2 Hz, 8.0 Hz), 7.66 (1H, dd, J=1.4 Hz, 7.6 Hz);IR (KBr) 3050-2650, 1688, 1426, 1306, 1279, 775, 764 cm¹; Anal. Calcdfor C₁₄H₁₆O₂: C, 77.75; H, 7.46. Found: C, 77.99; H, 7.34.

9)N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-5,5-dimethyl-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tettafluoroethoxy)phenyl]propan-1-ol(0.379 g, 1.049 mmol),5,5-dimethyl-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (0.23g, 1.05 mmol) and 1-hydroxybenzotriazole hydrate (0.16 g, 1.05 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.20 g, 1.05 mmol) was added and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solution,dried over anhydrous magnesium sulfate and passed through silica gel.The solvent was evaporated under reduced pressure and the obtainedresidue was crystallized from ethyl acetate-diisopropyl ether-hexane togive the objective substance.

white powder yield 0.545 g, 93% mp 101-104° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.28 (6H, s), 1.76 (2H, t, J=6.6 Hz), 2.36-2.45 (2H, m), 2.74 (1H, dd,J=10.6 Hz, 14.2 Hz), 3.00 (1H, dd, J=3.8 Hz, 14.4 Hz), 3.45 (1H, br s),4.65-4.79 (1H, m), 5.01 (1H, d, J=3.6 Hz), 5.69 (1H, d, J=9.4 Hz), 5.74(1H, td, J=4.2 Hz, 12.3 Hz), 5.89 (1H, tt, J=2.9 Hz, 53.3 Hz), 6.12 (1H,d, J=13.2 Hz), 6.77 (1H, d, J=6.6 Hz), 7.02-7.15 (6H, m), 7.26-7.40 (2H,m), 7.45 (2H, dd, J=5.3 Hz, 8.7 Hz); IR (KBr) 3357, 2965, 1638, 1505,1227, 1198, 1130 cm⁻¹; Anal. Calcd for C₃₁H₃₀F₅NO₃: C, 66.54; H, 5.40;N, 2.50. Found: C, 66.30; H, 5.50; N, 2.60.

Example 306N-[(1RS,2SR)-2-hydroxy-2-[4-(methylsulfonyl)phenyl]-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1) ethyl 3-[4-(methylsulfonyl)phenyl]-3-oxopropanoate

To a mixed solution of 4-(methylsulfonyl)acetophenone (10 g, 42.2 mmol),ethanol (0.2 ml) and diethyl carbonate (50 ml) was added sodium hydride(3.37 g, 60% in oil, 84.4 mmol) by small portions at room and themixture was stirred temperature for 2 hrs. and at 60° C. for 1 hr. Thereaction solution was cooled, 1N hydrochloric acid (30 ml) was added andthe mixture was extracted with ethyl acetate (100 ml). The extract waswashed with water, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The residue was purified by silica gelchromatography (hexane:ethyl acetate=3:1) to give the objectivesubstance (3.76 g, 33%) as crystals.

mp 50-52° C. IR ν max^(KBr)cm⁻:1738, 1622, 1427, 1304, 1250, 1198, 1148,1090. Anal. Calcd for C₁₂H₁₄O₅S (MW270.30) Calcd: C, 53.32; H, 5.22Found: C, 53.46; H, 5.25. ¹H-NMR (CDCl₃) δ: 1.27 (3H×1/2, t, J=7.1 Hz),1.36 (3H×1/2, t, J=7.1 Hz), 3.08 (3H×1/2, s), 3.10 (3H×1/2, s), 4.04(2H×1/2, q, J=7.1 Hz), 4.23 (2H×1/2, q, J=7.1 Hz), 5.76 (1H×1/2, s),7.95-8.20 (4H, m).

2) ethyl3-[4-(methylsulfonyl)phenyl]-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate

To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (2.84 ml, 16.8mmol) in ethyl acetate (30 ml) were added N-bromosuccinimide (3.0 g,16.8 mmol) and 2,2′-azobisisobutyronitrile (0.1 g) and the mixture washeated under reflux for 2 hrs. The reaction solution was concentratedunder reduced pressure and diethyl ether and hexane were added.Insoluble material was removed and washed with diethyl ether. Thefiltrate was evaporated under reduced pressure to give3-(1,1,2,2-tetrafluoroethoxy)-1-bromomethylbenzene. To a solution ofethyl 3-[4-(methylsulfonyl)phenyl]-3-oxopropanoate (3.5 g, 13.0 mmol) in1,2-dimethoxyethane (30 ml) was added sodium hydride (0.52 g, 60% inoil, 13.0 mmol) under ice-cooling and the mixture was stirred for 10min. A solution of 3-(1,1,2,2-tetrafluoroethoxy)-1-bromomethylbenzeneobtained above in 1,2-dimethoxyethane (5 ml) was dropwise added, and themixture was stirred at room temperature for 4 hrs. To the reactionsolution was added water (100 ml) and the mixture was extracted withethyl acetate (100 ml). The extract was washed with water, dried overanhydrous magnesium sulfate and evaporated under reduced pressure. Theresidue was purified by silica gel chromatography (hexane:ethylacetate=3:1-2:1) to give the objective substance (3.03 g, 49%) as anoil.

IR ν max^(Neat)cm⁻¹:1738, 1694, 1319, 1302, 1196, 1154, 1121. ¹H-NMR(CDCl₃) δ: 1.13 (3H, t, J=7.1 Hz), 3.07(3H, s), 3.37(2H, d, J=7.6 Hz),4.11(2H, q, J=7.1 Hz), 4.60(1H, t, J=7.6 Hz), 5.89(1H, tt, J=53.2, 3.0Hz), 7.00-7.35 (4H, m), 7.95-8.20(4H, m).

3) ethyl(2RS,3RS)-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate

To a suspension of zinc chloride anhydride (1.72 g, 12.6 mmol) indiethyl ether (20 ml) was added sodium borohydride (0.95 g, 25.2 mmol)by small portions, and the mixture was stirred for 1 hr. Insolublematerial was removed by filtration, and washed with diethyl ether. Thefiltrate was ice-cooled, and a solution of ethyl3-[4-(methylsulfonyl)phenyl]-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate(3.0 g, 6.30 mmol) in diethyl ether (10 ml) was added. The mixture wasstirred at room temperature for 1 hr. After ice-cooling again, 1Nhydrochloric acid was added to terminate the reaction. The obtainedmixture was extracted with ethyl acetate (100 ml), washed with water,dried over anhydrous magnesium sulfate and evaporated under reducedpressure. The residue was purified by silica gel chromatography(hexane:ethyl acetate=2:1-1:1) to give the objective substance (2.60 g,86%) as a colorless oil.

IR ν max^(Neat)cm⁻¹:1726, 1306, 1198, 1152, 1090, 774. ¹H-NMR (CDCl₃) δ:0.97(3H, t, J=7.1 Hz), 2.80-3.10(3H, m), 3.06(3H, s), 3.35(1H, d, J=2.6Hz), 3.95(2H, d, J=7.1 Hz), 5.15-5.25(1H, m), 5.89 (1H, tt, J=53.1, 3.0Hz), 6.85-7.10(3H, m), 7.21(1H, d, J=7.6 Hz), 7.61(2H, d, J=8.6 Hz),7.94(2H, d, J=8.6 Hz).

4)(2RS,3RS)-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoicacid

To a solution of ethyl(2RS,3RS)-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate(2.55 g, 5.33 mmol) in ethanol (20 ml) was added 1N aqueous sodiumhydroxide solution (10.7 ml, 10.7 mmol) and the mixture was stirred atroom temperature for 1 hr. 1N Hydrochloric acid (30 ml) was added toacidify the reaction solution and the mixture was extracted with ethylacetate (100 ml). The extract was washed with water, dried overanhydrous magnesium sulfate and evaporated under reduced pressure togive the objective substance (2.30 g, 96%) as an oil.

IR ν max^(Neat)cm⁻¹:1715, 1302, 1198, 1148, 1121, 1090, 961. ¹H-NMR(CDCl₃) δ: 2.80-3.05(2H, m), 3.05 (3H, s), 3.08(1H, d, J=4.0 Hz), 5.22(1H, d, J=4.0 Hz), 5.89(1H, tt, J=53.0, 2.8 Hz), 6.90-7.10(3H, m),7.22(1H, d, J=8.0 Hz), 7.60(2H, d, J=8.2 Hz), 7.90(2H, d, J=8.2 Hz).

5)(4RS,5SR)-5-[4-(methylsulfonyl)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoicacid (2.20 g, 4.88 mmol) in tetrahydrofuran (20 ml) were addeddiphenylphosphoryl azide (1.37 ml, 6.35 mmol) and triethylamine (0.95ml, 6.84 mmol) and the mixture was stirred at room temperature for 1 hr.After heating under reflux for 1 hr, water (100 ml) was added and themixture was extracted, with ethyl acetate (100 ml×2). The extract waswashed with saturated aqueous sodium hydrogen carbonate solution, driedover anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was purified by silica gel chromatography (hexane:ethylacetate=1:1-1:3). Hexane was added to the precipitated crystals and themixture was filtered to give the objective substance (2.07 g, 95%).

mp 123-125° C. IR ν max^(KBr)cm⁻:1740, 1588, 1314, 1152, 1115, 959.Anal. Calcd for C₁₉H₁₇F₄NO₅S (MW447.40) Calcd: C, 51.01; H, 3.83; N,3.13. Found: C, 50.87; H, 3.68; N, 2.98. ¹H-NMR (CDCl₃) δ: 2.20-2.40(2H,m), 3.10(3H, s), 4.25-4.45(1H, m), 5.10(1H, s), 5.89(1H, d, J=7.8 Hz),5.90(1H, tt, J=53.2, 3.0 Hz), 6.80-7.00(2H, m), 7.10-7.20(1H, m),7.34(1H, d, J=8.0 Hz), 7.60(2H, d, J=8.0 Hz).

6)(1RS,2SR)-2-amino-1-[4-(methylsulfonyl)phenyl]-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-1-propanol

To a solution of(4RS,5SR)-5-[4-(methylsulfonyl)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one(1.80 g, 4.02 mmol) in ethanol (20 ml) was added 8N aqueous sodiumhydroxide solution (1.51 ml, 12.07 mmol) and the mixture was heatedunder reflux for 3 hrs. To the reaction solution was added water (100ml) and the mixture was extracted with ethyl acetate (200 ml×2). Theextract was washed with water, dried over anhydrous magnesium sulfateand evaporated under reduced pressure. The residue was crystallized fromhexane-diethyl ether to give the objective substance (1.49 g, 86%).

mp 93-95° C. IR ν max^(KBr)cm⁻¹:1586, 1298, 1200, 1148, 1117, 766. Anal.Calcd for C₁₈H₁₉F₄NO₄S.1/2H₂O(MW430.42) Calcd: C, 50.22; H, 4.68; N,3.25. Found: C, 50.11; H, 4.43; N, 3.10. ¹H-NMR (CDCl₃) δ: 2.37(1H, dd,J=13.6, 10.2 Hz), 2.66(1H, dd, J=13.6, 2.8 Hz), 3.08(3H, s),3.30-3.50(1H, m), 4.81(1H, d, J=4.4 Hz), 5.90(1H, tt, J=53.1, 2.5 Hz),6.9-7.20(3H, m), 7.30-7.40(1H, m), 7.62(2H, d, J=8.2 Hz), 7.96(2H, d,J=8.2 Hz).

7)N-[(1RS,2SR)-2-hydroxy-2-[4-(methylsulfonyl)phenyl]-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-[4-(methylsulfonyl)phenyl]-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-1-propanol(0.301 g, 0.714 mmol), 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylicacid (0.13 g, 0.71 mmol) and 1-hydroxybenzotriazole hydrate (0.11 g,0.71 mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.14 g,0.71 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-ethyl acetate). Crystallizationfrom ethyl acetate-diisopropyl ether-hexane gave the objectivesubstance.

white powder yield 0.293 g, 69% mp 154-157° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.93-2.06 (2H, m), 2.15-2.24 (2H, m), 2.67 (2H, t, J=5.6 Hz), 2.80(1H, dd, J=11.8 Hz, 14.6 Hz), 2.95 (1H, dd, J=4.6 Hz, 14.4 Hz), 3.06(3H, s), 4.22 (1H, d, J=4.2 Hz), 4.62-4.75 (1H, m), 5.19 (1H, t, J=3.5Hz), 5.86 (1H, d, J=8.2 Hz), 5.89 (1H, tt, J=3.0 Hz, 53.1 Hz), 5.95 (1H,td, J=5.5 Hz, 11.8 Hz), 6.25 (1H, d, J=12.0 Hz), 6.97-7.35 (7H, m), 7.67(2H, d, J=8.4 Hz), 7.93 (2H, d, J=8.0 Hz); IR (KBr) 3486, 3330, 2932,1645, 1532, 1302, 1271, 1200, 1146, 1123, 768 cm⁻¹; Anal. Calcd forCHFNOS. 0.5H₂O: C, 59.99; H, 5.03; N, 2.33. Found: C, 60.02; H, 4.88; N,2.48.

Example 3071-(2-ethylbutyl)-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]cyclohexanecarboxamide.

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(0.335 g, 0.927 mmol), 1-(2-ethylbutyl)cyclohexanecarboxylic acid (0.22g, 1.02 mmol), 4-N,N-dimethylaminopyridine (0.11 g, 0.93 mmol) and1-hydroxybenzotriazole hydrate (0.14 g, 0.93 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.18g, 0.93 mmol) was added, and the mixture was stirred at 80° C. for 1day. The reaction solution was diluted with ethyl acetate, washed withaqueous sodium hydrogen carbonate solution and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography(hexane/ethyl acetate=3/1-2/1) to give the objective substance.

colorless liquid yield 0.416 g, 81% ¹H-NMR (CDCl₃, 300 MHz) δ 0.69-0.75(6H, m), 0.96-1.47 (15H, m), 1.64-1.76 (2H, m), 2.67 (1H, dd, J=11.0 Hz,14.6 Hz), 4.1 Hz, 14.6 Hz), 4.03 (1H, d, J=4.2 Hz), 4.42-4.50 (1H, m),4.98 (1H, t, J=3.0 Hz), 5.60 (1H, d, J=7.2 Hz), 5.88 (1H, tt, J=2.9 Hz,53.1 Hz), 6.97 (1H, s), 7.04-7.11 (4H, m), 7.28 (1H, t, J=8.0 Hz), 7.40(2H, dd, J=5.3 Hz, 8.6 Hz); IR (neat) 3378, 2932, 2861, 1636, 1609,1508, 1449, 1304, 1279, 1223, 1196, 1123 cm⁻¹

Example 308 methyl4-[(1RS,2SR)-2-[(tert-butoxycarbonyl)amino]-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl]benzoate

1) benzyl 3-[4-(methoxycarbonyl)phenyl]-3-oxopropionate

To a solution of 4-(methoxycarbonyl)benzoic acid (50.95 g, 282.8 mmol)in tetrahydrofuran (400 ml) was added 1,1′-carbonyldiimidazole (50.4 g,311 mmol) at room temperature and the mixture was stirred as it was for2 hrs. Dimethyl sulfoxide (200 ml), monobenzyl malonate monopotassiumsalt (78.8 g, 339 mmol) and sodium magnesium (16.2 g, 170 mmol) wereadded at room temperature, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate andwater and acidified with conc. hydrochloric acid. The ethyl acetatelayer was separated and the aqueous layer was extracted with ethylacetate. The recovered organic layer was dried over anhydrous sodiumsulfate and the solvent was evaporated under reduced pressure. Theobtained crude product was purified by silica gel column chromatography(hexane/ethyl acetate=3/1-2/1) to give the objective substance.

pale-yellow solid yield 31.19 g, 35%

Recrystallization from ethyl acetate-diethyl ether-hexane gavepale-yellow crystals.

mp 74-75° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 3.94 (1.2H, s), 3.96 (1.8H, s),4.07 (1.2 Hz, s), 5.20 (1.2H, s), 5.27 (0.8H, s), 5.80 (0.4H, s),7.22-7.43 (5H, m), 7.84 (0.8H, d, J=8.8 Hz), 7.97 (1.2H, d, J=8.4 Hz),8.08 (0.8H, d, J=8.0 Hz), 8.12 (1.2H, d, J=8.8 Hz); IR (KBr) 1721, 1281,1211, 1204, 1109, 818, 731 cm⁻¹; Anal. Calcd for C₁₈H₁₆O₅: C, 69.22; H,5.16. Found: C, 69.40; H, 5.24.

2) benzyl3-[4-(methoxycarbonyl)phenyl]-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate

3-(1,1,2,2-Tetrafluoroethoxy)toluene (48.4 g, 233 mmol),N-bromosuccinimide (41.4 g, 233 mmol) and 2,2′-azobis(isobutyronitrile)(0.1 g) were heated under reflux in carbon tetrachloride (100 ml) for0.5 hr. After cooling the reaction solution to room temperature, thewhite precipitate was removed by filtration, and the precipitate waswashed with diethyl ether. The solvent of the recovered filtrate wasevaporated under reduced pressure to give a crude product of3-(1,1,2,2-tetrafluoroethoxy)benzyl bromide as a pale-yellow liquid.

To a solution of benzyl 3-[4-(methoxycarbonyl)phenyl]-3-oxopropionate(66.08 g, 211.6 mmol) in 1,2-dimethoxyethane (200 ml) was added asuspension (8.89 g, 222 mmol) of 60% sodium hydride in liquid paraffinunder ice-cooling, and the mixture was stirred as it was for 0.5 hr. Asolution of 3-(1,1,2,2-tetrafluoroethoxy)benzyl bromide obtained abovein 1,2-dimethoxyethane (50 ml) was added at room temperature and themixture was stirred overnight at room temperature. The reaction solutionwas poured into water, and extracted twice with ethyl acetate. Therecovered organic layer was dried over anhydrous magnesium sulfate andthe solvent was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (hexane/ethylacetate=3/1-2/1) to give the objective substance.

pale-yellow liquid yield 98.99 g, 90% ¹H-NMR (CDCl₃, 300 MHz) δ 3.36(2H, d, J=7.2 Hz), 3.95 (3H, s), 4.63 (1H, t, J=7.4 Hz), 5.03 (1H, d,J=16.8 Hz), 5.08 (1H, d, J=15.9 Hz), 5.88 (1H, tt, J=2.7 Hz, 53.1 Hz),7.01-7.49 (9H, m), 7.93 (2H, d, J=8.4 Hz), 8.05 (2H, d, J=8.1 Hz); IR(neat) 1728, 1694, 1281, 1196, 1119 cm⁻¹

3) benzyl(2RS,3RS)-3-hydroxy-3-[4-(methoxycarbonyl)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate

While stirring zinc chloride (52.0 g, 382 mmol) in diethyl ether (250ml), sodium borohydride (28.9 g, 764 mmol) was added at room temperatureand the mixture was stirred as it was for 2 hrs. Insoluble material inthe mixture was removed by filtration and washed with diethyl ether togive a solution of zinc borohydride in diethyl ether. A solution ofbenzyl3-[4-(methoxycarbonyl)phenyl]-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate(98.98 g, 190.9 mmol) in diethyl ether (100 ml) was added dropwise tothe obtained solution under ice-cooling, and the mixture was stirred asit was for 1 hr. To the reaction solution was added dilute hydrochloricacid by small portions to decompose excess zinc borohydride, and themixture was extracted twice with ethyl acetate. The recovered organiclayer was dried over anhydrous magnesium sulfate and the solvent wasevaporated under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (hexane/ethylacetate=6/1−2/1) to give the objective substance.

colorless liquid yield 69.90 g yield 70% ¹H-NMR (CDCl₃, 300 MHz) δ2.93-3.10 (4H, m), 3.92 (3H, s), 4.83 (1H, d, J=12.3 Hz), 4.89 (1H, d,J=12.3 Hz), 5.11 (1H, t, J=3.6 Hz), 5.87 (1H, tt, J=2.9 Hz, 53.2 Hz),6.91-7.03 (5H, m), 7.16-7.38 (4H, m), 7.44 (2H, d, J=8.4 Hz), 7.99 (2H,d, J=8.4 Hz); IR (neat) 3480, 1723, 1281, 1196, 1119 cm⁻¹

4)(4RS,5SR)-5-[4-(methoxycarbonyl)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one

A solution of benzyl(2RS,3RS)-3-hydroxy-3-[4-(methoxycarbonyl)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate(69.90 g, 134.3 mmol) in ethanol (200 ml) was hydrogenated overnightusing 10% palladium/carbon (containing water by 50%). (5 g) as acatalyst under normal pressure. The catalyst was removed by filtration,washed with ethanol, and the solvent of the recovered filtrate wasevaporated under reduced pressure to give crude(2RS,3RS)-3-hydroxy-3-[4-(methoxycarbonyl)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionicacid as a colorless foam.

The foam obtained above was dissolved in tetrahydrofuran (150 ml), andtriethylamine (22.5 ml, 161 mmol) and diphenylphosphoryl azide (40.7 g,148 mmol) were added. The mixture was stirred at 70° C. overnight. Thesolvent of the reaction solution was evaporated under reduced pressureand the obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-ethyl acetate). Crystallizationfrom N,N-dimethylformamide-diisopropyl ether gave the objectivesubstance.

white powder yield 40.33 g, 70% mp 155-158° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 2.17-2.34 (2H, m), 3.95 (3H, s), 4.25-4.36 (1H, m), 5.07 (1H, br s),5.87 (1H, d, J=7.8 Hz), 5.89 (1H, tt, J=2.8 Hz, 53.0 Hz), 6.85 (1H, s),6.94 (1H, d, J=7.8 Hz), 7.10 (1H, d, J=8.4 Hz), 7.30 (1H, t, J=8.0 Hz),7.46 (2H, d, J=8.0 Hz), 8.11 (2H, d, J=8.4 Hz); IR (KBr) 3250, 1736,1279, 1206, 1113 cm⁴; Anal. Calcd for C₂₀H₁₇F₄NO₅.0.5DMF: C, 55.67; H,4.45; N, 4.53. Found: C, 55.60; H, 4.18; N, 4.83.

5) tert-butyl(4RS,5SR)-5-[4-(methoxycarbonyl)phenyl]-2-oxo-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate

A solution of(4RS,5SR)-5-[4-(methoxycarbonyl)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one(20.04 g, 46.89 mmol), di-tert-butyl dicarbonate (12.3 g, 56.3 mmol) and4-N,N-dimethylaminopyridine (0.57 g, 4.69 mmol) in acetonitrile (150 ml)was stirred overnight at room. temperature. The solvent of the reactionsolution was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (hexane/ethylacetate=3/1-2/1). Crystallization from ethyl acetate-diisopropylether-hexane gave the objective substance.

white crystal yield 21.14 g, 86% mp 140-141° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.52 (9H, s), 2.59 (1H, dd, J=8.9 Hz, 14.3 Hz), 2.91 (1H, dd, J=4.2Hz, 14.1 Hz), 3.93 (3H, s), 4.81-4.88 (1H, m), 5.73 (1H, d, J=6.9 Hz),5.85 (1H, tt, J=2.9 Hz, 53.1 Hz), 6.35 (1H, s), 6.62 (1H, d, J=7.5 Hz),6.95 (1H, d, J=8.7 Hz), 7.06 (1H, t, J=8.0 Hz), 7.24 (2H, d, J=8.1 Hz),7.93 (2H, d, J=8.7 Hz); IR (KBr) 17.86, 1717, 1360, 1331, 1281, 1200,1113, 1071 cm⁻¹; Anal. Calcd for C₂₅H₂₅F₄NO₇: C, 56.93; H, 4.78; N,2.66. Found: C, 57.05; H, 4.76; N, 2.71.

6) methyl4-[(1RS,2SR)-2-[(tert-butoxycarbonyl)amino]-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl]benzoate

To a solution of tert-butyl(4RS,5SR)-5-[4-(methoxycarbonyl)phenyl]-2-oxo-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate(20.82 g, 39.47 mmol) in methanol (50 ml)-tetrahydrofuran (100 ml) wasadded a solution of sodium hydroxide (1.66 g, 41.4 mmol) in methanol (20ml) under ice-cooling and the mixture was stirred at room temperaturefor 10 min. The reaction solution was diluted with ethyl acetate, washedwith water, dried over anhydrous magnesium sulfate and passed throughsilica gel. The solvent was evaporated under reduced pressure. Theobtained residue was crystallized from ethyl acetate-hexane to give theobjective substance.

white crystal yield 16.05 g, 81% mp 148-150° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.36 (9H, s), 2.73 (2H, d, J=6.0 Hz), 3.45 (1H, br s), 3.93 (3H, s),4.05-4.11 (1H, m), 4.61 (1H, br d, J=8.4 Hz), 5.03 (1H, br s), 5.89 (1H,tt, J=2.9 Hz, 53.1 Hz), 6.94 (1H, s), 7.00 (1H, d, J=7.5 Hz), 7.05 (1H,dd, J=1.4 Hz, 8.3 Hz), 7.26 (1H, t, J=8.0 Hz), 7.49 (2H, d, J=8.1 Hz),8.05 (2H, d, J=8.4 Hz); IR (KBr) 3330, 3206, 1721, 1678, 1551, 1300,1283, 1202, 1175, 1113, 1098 cm⁻¹; Anal. Calcd for C₂₄H₂₇F₄NO₆: C,57.48; H, 5.43; N, 2.79. Found: C, 57.43; H, 5.71; N, 2.62.

Example 309 methyl4-[(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a]cyclohepten-1-ylcarbonyl)amino]-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl]benzoate

1) methyl4-[(1RS,2SR)-2-amino-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl]benzoate

A solution of methyl4-[(1RS,2SR)-2-[(tert-butoxycarbonyl)amino]-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl]benzoate(15.72 g, 31.35 mmol) and conc. hydrochloric acid (10 ml) in methanol(150 ml) was stirred at 60° C. for 1 hr. The reaction solution wasconcentrated under reduced pressure, diluted with water, alkalified withpotassium carbonate, and extracted twice with ethyl acetate. Therecovered organic layer was dried over anhydrous sodium sulfate and thesolvent was evaporated under reduced pressure. The residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white crystal yield 12.27 g, 98% mp 100-101° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 2.37 (1H, dd, J=10.5 Hz, 13.8 Hz), 2.72 (1H, dd, J=3.2 Hz, 13.7 Hz),3.34 (1H, ddd, J=3.4 Hz, 4.3 Hz, 10.4 Hz), 3.93 (3H, s), 4.77 (1H, d,J=4.5 Hz), 5.89 (1H, tt, J=2.8 Hz, 53.3 Hz), 6.97 (1H, s), 7.02-7.09(2H, m), 7.29 (1H, t, J=7.8 Hz), 7.48 (2H, d, J=8.1 Hz), 8.06 (2H, d,J=8.4 Hz); IR (KBr) 3.150-2850, 1725, 1281, 1198, 1111 cm⁻¹; Anal. Calcdfor C₁₉H₁₉F₄NO₄: C, 56.86; H, 4.77; N, 3.49. Found: C, 56.68; H, 4.92;N, 3.26.

2) methyl4-[(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a]cyclohepten-1-ylcarbonyl)amino]-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl]benzoate

While stirring methyl4-[(1RS,2SR)-2-amino-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl]benzoate(10.80 g, 26.91 mmol), 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylicacid (5.06 g, 26.9 mmol) and 1-hydroxybenzotriazole hydrate (4.12 g,26.9 mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.16 g,26.9 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from diisopropyl ether to give the objective substance.

white crystal yield 13.24 g, 86% mp 137-138° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.98-2.04 (2H, m), 2.16-2.22 (2H, m), 2.66 (2H, t, J=5.9 Hz), 2.80(1H, dd, J=10.8 Hz, 14.4 Hz), 2.95 (1H, dd, J=4.4 Hz, 14.6 Hz), 3.86(1H, d, J=4.2 Hz), 3.93 (3H, s), 4.66-4.72 (1H, m), 5.15 (1H, t, J=3.8Hz), 5.79 (1H, d, J=8.4 Hz), 5.88 (1H, tt, J=2.9 Hz, 53.1 Hz), 5.92 (1H,td, J=5.7 Hz, 11.4 Hz), 6.23 (1H, d, J=11.4 Hz), 6.97-7.11 (5H, m), 7.16(1H, dd, J=1.1 Hz, 7.4 Hz), 7.29 (1H, t, J=8.0 Hz), 7.55 (2H, d, J=8.4Hz), 8.06 (2H, d, J=8.1 Hz); IR (Kr) 3256, 2934, 1719, 1636, 1528, 1439,1285, 1194, 1115, 775 cm⁻¹; Anal. Calcd for C₃₁H₂₉F₄NO₅: C, 65.14; H,5.11; N, 2.45. Found: C, 64.98; H, 5.39; N, 2.35.

Example 3104-[(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a]cyclohepten-1-ylcarbonyl)amino]-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl]benzoicacid

To a solution of methyl4-[(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a]cyclohepten-1-ylcarbonyl)amino]-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl]benzoate(12.93 g, 22.62 mmol) in methanol (40 ml)-tetrahydrofuran (50 ml) wasadded 1N aqueous sodium hydroxide solution (67.9 ml, 67.9 mmol) and themixture was stirred overnight at room temperature. The reaction solutionwas concentrated, diluted with water, acidified with dilute hydrochloricacid, and extracted twice with ethyl acetate. The recovered organiclayer was dried over anhydrous sodium sulfate and the solvent wasevaporated under reduced pressure. The obtained solid was washed withethyl acetate-diisopropyl ether to give the objective substance.

white powder yield 10.52 g, 83% mp 210-211° C.; ¹H-NMR (CDCl₃-DMSO-d₆,300 MHz) δ 1.92-2.00 (2H, m), 2.18-2.26 (2H, m), 2.65-2.69 (2H, m),2.82-2.93 (2H, m), 4.64-4.74 (1H, m), 5.03 (1H, d, J=3.6 Hz), 5.31 (1H,br s), 5.85 (1H, td, J=5.3 Hz, 11.8 Hz), 5.98 (1H, tt, J=3.0 Hz, 53.1Hz), 6.14 (1H, d, J=11.7 Hz), 6.89 (1H, dd, J=1.5 Hz, 7.8 Hz), 7.01-7.13(5H, m), 7.26 (1H, t, J=8.1 Hz), 7.61 (2H, d, J=8.4 Hz), 8.05 (2H, d,J=8.1 Hz); IR (KBr) 3268, 3020-2860, 1686, 1640, 1279, 1202, 1123 cm⁻¹;Anal. Calcd for C₃₀H₂₇F₄NO₅: C, 64.63; H, 4.88; N, 2.51. Found: C,64.50; H, 4.80; N, 2.39.

Example 311N-[(1RS,2SR)-2-[4-(aminocarbonyl)phenyl]-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring4-[(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a]cyclohepten-1-ylcarbonyl)amino]-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl]benzoicacid (0.284 g, 0.509 mmol) and 1-hydroxybenzotriazole hydrate (86 mg,0.56 mmol) in acetonitrile (10 ml)-N,N-dimethylformamide (2 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g,0.56 mmol) was added and the mixture was stirred at room temperature for0.5 hr. Thereto were added ammonium chloride (54 mg, 1.02 mmol) andtriethylamine (0.21 ml, 1.53 mmol) and the mixture was stirred at roomtemperature for 1 hr. To the reaction solution was added aqueous sodiumhydrogen carbonate solution, and the mixture was stirred at roomtemperature for 0.5 hr. The recovered precipitate was washed with waterand diisopropyl ether-hexane to give the objective substance.

white powder yield 0.227 g, 80% mp 197-199° C.; ¹H-NMR (CDCl₃-DMSO-d₆,300 MHz) δ 1.91-1.99 (2H, m), 2.20-2.25 (2H, m), 2.67 (2H, t, J=5.6 Hz),2.81-2.95 (2H, m), 4.64-4.73 (1H, m), 5.01 (1H, d, J=4.2 Hz), 5.35 (1H,br s), 5.84 (1H, td, J=5.1 Hz, 11.7 Hz), 6.00 (1H, tt, J=2.9 Hz, 53.0Hz), 6.11 (1H, d, J=12.0 Hz), 6.29 (1H, br s), 6.87 (1H, dd, J=1.5 Hz,7.5 Hz), 7.00-7.14 (5H, m), 7.22-7.29 (2H, m), 7.61 (2H, d, J=8.1 Hz),7.91 (2H, d, J=8.4 Hz); IR (KBr) 3310, 1636, 1615, 1524, 1206, 1121, 777cm⁻¹; Anal. Calcd for C₃₀H₂₈F₄N₂O₄.0.5H₂O: C, 63.71; H, 5.17; N, 4.95.Found: C, 63.68; H, 5.30; N, 4.88.

Example 312N-[(1RS,2SR)-2-[4-[(dimethylamino)carbonyl]phenyl]-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

Using dimethylamine hydrochloride as amine and in the same manner as inExample 311, the objective substance (0.244 g, 82%) was obtained as awhite powder.

mp 165-166° C.; ¹H-NMR (CDCl₃, 300 MHz) δ 1.96-2.05 (2H, m), 2.16-2.22(2H, m), 2.66 (2H, t, J=5.9 Hz), 2.75 (1H, dd, J=10.8 Hz, 14.7 Hz), 2.93(1H, dd, J=3.9 Hz, 15.6 Hz), 2.97 (3H, s), 3.11 (3H, s), 4.41 (1H, d,J=4.2 Hz), 4.67-4.74 (1H, m), 5.03 (1H, t, J=3.8 Hz), 5.86 (1H, d, J=8.4Hz), 5.89 (1H, tt, J=2.7 Hz, 53.1 Hz), 5.94 (1H, td, J=5.6 Hz, 11.3 Hz),6.26 (1H, d, J=12.0 Hz), 6.99-7.17 (6H, m), 7.29 (1H, t, J=8.1 Hz), 7.38(2H, d, J=8.1 Hz), 7.45 (2H, d, J=8.1 Hz); IR (KBr) 3326, 2942, 1638,1620, 1518, 1194, 1115 cm⁻¹; Anal. Calcd for C₃₂H₃₂F₄N₂O₄: C, 65.74; H,5.52; N, 4.79. Found: C, 65.58; H, 5.63; N, 4.81.

Example 313N-[(1RS,2SR)-2-hydroxy-2-[4-(piperidinocarbonyl)phenyl]-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

Using piperidine as amine and in the same manner as in Example 311, theobjective substance (0.275 g, 86%) was obtained as white crystals.

mp 176-177° C.; ¹H-NMR (CDCl₃, 300 MHz) δ 1.51 (2H, br s), 1.68 (4H, brs), 1.96-2.04 (2H, m), 2.16-2.22 (2H, m), 2.66 (2H, t, J=5.9 Hz), 2.75(1H, dd, J=10.7 Hz, 14.6 Hz), 2.95 (1H, dd, J=3.9 Hz, 14.7 Hz), 3.32(2H, br s), 3.70 (2H, br s), 4.36 (1H, d, J=3.6 Hz), 4.67-4.75 (1H, m),5.03 (1H, t, J=3.8 Hz), 5.82 (1H, d, J=8.1 Hz), 5.89 (1H, tt, J=2.9 Hz,53.2 Hz), 5.94 (1H, td, J=5.7 Hz, 11.3 Hz), 6.25 (1H, d, J=11.7 Hz),6.99-7.17 (6H, m), 7.29 (1H, t, J=7.8 Hz), 7.36 (2H, d, J=8.1 Hz), 7.45(2H, d, J=8.1 Hz); IR (KBr) 3430, 3328, 2940, 2863, 1640, 1516, 1437,1277, 1209, 1123, 768 cm⁻¹; Anal. Calcd for C₃₅H₃₆F₄N₂O₄: C, 67.30; H,5.81; N, 4.48. Found: C, 67.20; H, 5.78; N, 4.47.

Example 314N-[(1RS,2SR)-2-[4-(anilinocarbonyl)phenyl]-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

Using aniline as amine and in the same manner as in Example 311, theobjective substance (0.275 g, 85%) was obtained as a white powder.

mp 205-206° C.; ¹H-NMR (CDCl₃-DMSO-d₆, 300 MHz) δ 1.94-2.00 (2H, m),2.19-2.25 (2H, m), 2.67 (2H, t, J=5.4 Hz), 2.88 (2H, d, J=7.5 Hz),4.68-4.76 (1H, m), 5.06 (1H, t, J=3.5 Hz), 5.25 (1H, d, J=3.6 Hz), 5.88(1H, td, J=5.6 Hz, 11.4 Hz), 5.95 (1H, tt, J=2.9 Hz, 53.0 Hz), 6.17 (1H,d, J=11.4 Hz), 6.92 (1H, dd, J=1.1 Hz, 7.4 Hz), 7.01-7.13 (7H, m), 7.27(1H, t, J=8.3 Hz), 7.35 (2H, t, J=7.8 Hz), 7.64 (2H, d, J=8.4 Hz), 7.76(2H, d, J=7.8 Hz), 7.99 (2H, d, J=8.4 Hz), 9.31 (1H, s); IR (KBr) 3297,2938, 1647, 1532, 1507, 1443, 1323, 1200, 1121, 752, 694 cm⁻¹; Anal.Calcd for C₃₆H₃₂F₄N₂O₄: C, 68.35; H, 5.10; N, 4.43. Found: C, 68.10; H,5.07; N, 4.42.

Example 315N-[(1RS,2SR)-2-hydroxy-2-[4-[(isopropylamino)carbonyl]phenyl]-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

Using isopropylamine as amine and in the same manner as in Example 311,the objective substance (0.258 g, 84%) was obtained as a white powder.

mp 215-217° C.; ¹H-NMR (CDCl₃-DMSO-d₆, 300 MHz) δ 1.27 (6H, d, J=6.6Hz), 1.93-2.02 (2H, m), 2.19-2.25 (2H, m), 2.67 (2H, t, J=5.1 Hz), 2.85(2H, d, J=7.5 Hz), 4.25-4.32 (1H, m), 4.67-4.75 (1H, m), 5.06 (2H, s),5.88 (1H, td, J=5.7 Hz, 11.4 Hz), 5.92 (1H, tt, J=3.0 Hz, 53.0 Hz), 6.18(1H, d, J=12.0 Hz), 6.46 (1H, d, J=7.8 Hz), 6.80 (1H, d, J=9.0 Hz), 6.94(1H, dd, J=1.2 Hz, 7.5 Hz), 7.01-7.14 (5H, m), 7.26 (1H, t, J=7.8 Hz),7.58 (2H, d, J=8.4 Hz), 7.80 (2H, d, J=8.4 Hz); IR (KBr) 3295, 2971,2930, 1638, 1537, 1213, 1123 cm⁻¹; Anal. Calcd for C₃₃H₃₄F₄N₂O₄: C,66.21; H, 5.72; N, 4.68. Found: C, 66.00; H, 5.50; N, 4.65.

Example 316N-[(1RS,2SR)-2-[4-[(benzylamino)carbonyl]phenyl]-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

Using benzylamine as amine and in the same manner as in Example 311, theobjective substance (0.297 g, 90%) was obtained as a white powder.

mp 216-217° C.; ¹H-NMR (CDCl₃-DMSO-d₆, 300 MHz) δ 1.91-1.99 (2H, m),2.19-2.24 (2H, m), 2.67 (2H, t, J=5.9 Hz), 2.86-2.89 (2H, m), 4.62 (2H,d, J=6.0 Hz), 4.65-4.71 (1H, m), 5.01 (1H, t, J=3.8 Hz), 5.30 (1H, d,J=3.3 Hz), 5.84 (1H, td, J=5.5 Hz, 11.3 Hz), 5.99 (1H, tt, J=2.8 Hz,52.9 Hz), 6.11 (1H, d, J=12.0 Hz), 6.88 (1H, dd, J=1.2 Hz, 7.5 Hz),7.00-7.05 (3H, m), 7.11 (2H, d, J=9.9 Hz), 7.17-7.39 (7H, m), 7.60 (2H,d, J=8.1 Hz), 7.93 (2H, d, J=8.1 Hz), 8.05 (1H, t, J=5.6 Hz); IR (KBr)3297, 2932, 1638, 1615, 1537, 1200, 1130, 698 cm⁻¹; Anal. Calcd forC₃₇H₃₄F₄N₂O₄: C, 68.72; H, 5.30; N, 4.33. Found: C, 68.59; H, 5.06; N,4.22.

Example 317N-[(1RS,2SR)-2-[4-[(butylamino)carbonyl]phenyl]-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

Using butylamine as amine and in the same manner as in Example 311, theobjective substance (0.284 g, 91%) was obtained as a white powder.

mp 207-208° C.; ¹H-NMR (CDCl₃-DMSO-d₆, 300 MHz) δ 0.96 (3H, t, J=7.4Hz), 1.35-1.48 (2H, m), 1.56-1.66 (2H, m), 1.94-2.01 (2H, m), 2.20-2.26(2H, m), 2.68 (2H, t, J=6.0 Hz), 2.87 (2H, d, J=8.4 Hz), 3.42 (2H, q,J=6.7 Hz), 4.64-4.72 (1H, m), 5.03 (1H, t, J=3.8 Hz), 5.23 (1H, d, J=3.6Hz), 5.86 (1H, td, J=5.2 Hz, 12.1 Hz), 5.97 (1H, tt, J=2.9 Hz, 53.0 Hz),6.14 (1H, d, J=11.7 Hz), 6.90 (1H, dd, J=1.2 Hz, 7.5 Hz), 7.01-7.17 (7H,m), 7.26 (1H, t, J=8.3 Hz), 7.59 (2H, d, J=7.8 Hz), 7.84 (2H, d, J=8.4Hz); IR (KBr) 3308, 2934, 1640, 1612, 1537, 1201, 1128, 696. cm⁻¹; Anal.Calcd for C₃₄H₃₆F₄N₂O₄: C, 66.66; H, 5.92; N, 4.57. Found: C, 66.44; H,5.8.8; N, 4.40.

Example 318N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-4-methyl-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1) ethyl (E)-5-(2-methylphenyl)-3-oxo-4-pentenoate

To a solution of 2-methylcinnamic acid (50.71 g, 312.7 mmol) intetrahydrofuran (500 ml) was added 1,1′-carbonyldiimidazole (55.8 g, 344mmol) at room temperature, and the mixture was stirred as it was for 1hr. To the mixture were added monoethyl malonate monopotassium salt(58.5 g, 344 mmol) and magnesium chloride (16.4 g, 172 mmol) at roomtemperature, and the mixture was stirred at 60° C. overnight. Thereaction solution was diluted with ethyl acetate and water and acidifiedwith conc. hydrochloric acid. The ethyl acetate layer was separated, andthe aqueous layer was extracted with ethyl acetate. The recoveredorganic layer was dried over anhydrous sodium sulfate and the solventwas evaporated under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (hexane/ethylacetate=9/1-6/1) to give the objective substance.

yellow liquid yield 37.24 g, 51% ¹H-NMR (CDCl₃, 200 MHz) δ 1.29 (1.2H,t, J=7.1 Hz), 1.32 (1.8H, t, J=7.1 Hz), 2.43 (1.8H, s), 2.45 (1.2H, s),3.70 (0.8H, s), 4.23 (0.8H, q, J=7.2 Hz), 4.24 (1.2H, q, J=7.1 Hz), 5.17(0.6H, s), 6.36 (0.6H, dd, J=1.4 Hz, 15.8 Hz), 6.74 (0.4H, d, J=15.8Hz), 7.15-7.35 (3H, m), 7.52-7.61 (1H, m), 7.70 (0.6H, d, J=15.8 Hz),7.93 (0.4H, d, J=16.2 Hz); IR (neat) 2980, 1740, 1636, 1595, 1420, 1236,1148, 1038, 754 cm⁻¹

2) ethyl 5-(2-methylphenyl)pentanoate

To a solution of ethyl (E)-5-(2-methylphenyl)-3-oxo-4-pentenoate (37.24g, 160.3 mmol) in ethanol (100 ml) was added sodium borohydride (3.03 g,80.2 mmol) by small portions under ice-cooling, and the mixture wasstirred as it was for 10 min. The reaction solution was diluted withwater, and extracted twice with ethyl acetate. The recovered organiclayer was dried over anhydrous sodium sulfate and the solvent wasevaporated under reduced pressure to give a crude product of ethyl(E)-3-hydroxy-5-(2-methylphenyl)penta-4-enoate as a yellow liquid.

To a solution of the liquid obtained above and triethylamine (33.5 ml,240 mmol) in ethyl acetate (180 ml) was dropwise added methanesulfonylchloride (22.0 g, 192 mmol) under ice-cooling, and the mixture wasstirred as it was for 15 min. The resulting precipitate (triethylaminehydrochloride) was removed by filtration, and washed with ethyl acetate.The recovered ethyl acetate solution was concentrated under reducedpressure. The obtained residue was dissolved in tetrahydrofuran (200 ml)and 1,8-diazabicyclo[5.4.0]-7-undecene (28.8 ml, 192 mmol) was added.The mixture was stirred at room temperature for 0.5 hr. The reactionsolution was poured into water, and extracted twice with ethyl acetate.The recovered organic layer was dried over anhydrous magnesium sulfateand the solvent was evaporated under reduced pressure. The obtainedcrude product was purified by silica gel column chromatography(hexane/ethyl acetate=15/1-9/1) to give ethyl5-(2-methylphenyl)penta-2,4-dienoate (a mixture of (2E,4E) form and(2Z,4E) form) as a yellow liquid.

A solution of the liquid obtained above in ethanol (40 ml) washydrogenated at normal temperature and under normal pressure using 10%palladium/carbon. (containing water by 50%) (1.5 g) as a catalyst untilthe starting material disappeared. The catalyst was removed byfiltration and the solvent was evaporated under reduced pressure. Theobtained crude product was purified by silica gel column chromatography(hexane/ethyl acetate=15/1-6/1) to give the objective substance.

colorless liquid yield 13.92 g, 39% ¹H-NMR (CDCl₃, 200 MHz) δ 1.25. (3H,t, J=7.2 Hz), 1.52-1.80 (4H, m), 2.30 (3H, s), 2.34 (2H, t, J=7.0 Hz),2.61 (2H, t, J=7.6 Hz), 4.12 (2H, q, J=7.2 Hz), 7.12 (4H, s); IR (neat)2938, 1736, 1181, 745 cm⁻¹

3) 5-(2-methylphenyl)pentanoic acid

A mixture of ethyl 5-(2-methylphenyl)pentanoate (13.92 g, 63.18 mmol),sodium hydroxide (5.05 g, 126 mmol), water (30 ml), methanol (50 ml) andtetrahydrofuran (50 ml) was stirred overnight at room temperature. Thereaction solution was concentrated, diluted with water, and washed withdiethyl ether. The obtained aqueous solution was acidified with conc.hydrochloric acid, and extracted twice with ethyl acetate. The recoveredorganic layer was dried over anhydrous sodium sulfate and the solventwas evaporated under reduced pressure to give the objective substance.

white crystal yield 12.04 g, 99% mp 57-58° C.; ¹H-NMR (CDCl₃, 200 MHz) δ1.54-1.82 (4H, m), 2.30 (3H, s), 2.40 (2H, t, J=7.1 Hz), 2.62 (2H, t,J=7.6 Hz), 7.12 (4H, s); IR (KBr) 3070-2520, 1698, 1462, 1437, 1406,1329, 1289, 1260, 1208, 941, 739 cm⁻¹

4) 1-methyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one

To a solution of 5-(2-methylphenyl)pentanoic acid (11.92 g, 62.00 mmol)and N,N-dimethylformamide (2 drops) in tetrahydrofuran (50 ml) wasdropwise added oxalyl chloride (8.11 ml, 93.0 mmol) at room temperature,and the mixture was stirred as it was for 0.5 hr. The solvent of thereaction mixture was evaporated under reduced pressure to give acidchloride as a yellow liquid.

While stirring a suspension of aluminum chloride (16.5 g, 124 mmol) inmethylene chloride (100 ml), a solution of acid chloride obtained abovein methylene chloride (250 ml) was dropwise added over 1 day. Whileice-cooling the reaction solution, water was added to terminate thereaction. The methylene chloride layer of the mixture was separated, andthe aqueous layer was extracted with diethyl ether. The recoveredorganic layer was dried over anhydrous magnesium sulfate and the solventwas evaporated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=9/1) to givethe objective substance.

pale-yellow solid yield 10.14 g, 94%

Recrystallization from hexane gave white crystals.

mp 65-66° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 1.69-1.91 (4H, m), 2.37 (3H, s),2.67 (2H, t, J=5.9 Hz), 2.88 (2H, t, J=6.2 Hz), 7.17 (1H, t, J=7.5 Hz),7.30 (1H, d, J=6.6 Hz), 7.44 (1H, d, J=7.4 Hz); IR (KBr) 2940, 1671,1586, 1460, 1271, 793 cm⁻¹; Anal. Calcd for C₁₂H₁₄O: C, 82.72; H, 8.10.Found: C, 82.68; H, 8.15.

5) 1-methyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol

To a solution of1-methyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one (9.797 g, 56.23mmol) in methanol (40 ml) was added sodium borohydride (2.13 g, 56.2mmol) by small portions under ice-cooling and the mixture was stirred atroom temperature for 1 hr. The reaction solution was diluted with water,and extracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous magnesium sulfate and the solvent was evaporatedunder-reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=6/1). Crystallization fromethyl acetate-hexane gave the objective substance.

white crystal yield 8.345 g, 84% mp 109-110° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.30-1.42 (1H, m), 1.66-1.86 (4H, m), 1.91-2.05 (2H, m), 2.32 (3H, s),2.57 (1H, dd, J=11.1 Hz, 12.9 Hz), 3.08 (1H, ddd, J=1.6 Hz, 7.9 Hz, 14.5Hz), 5.01 (1H, dd, J=3.6 Hz, 9.0 Hz), 7.06 (1H, dd, J=1.7 Hz, 7.7 Hz),7.11 (1H, t, J=7.4 Hz), 7.32 (1H, d, J=6.9 Hz); IR (KBr) 3293, 3189,2928, 1466, 1439, 1096, 1049, 781, 747 cm⁻¹; Anal. Calcd for C₁₂H₁₆O: C,81.77; H, 9.15. Found: C, 81.73; H, 8.93.

6) 4-bromo-1-methyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol

To a solution of 1-methyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol(8.193 g, 46.48 mmol) and N,N,N′,N′-tetramethylethylenediamine (11.9 g,102 mmol) in hexane (100 ml) was added a solution of 1.6 Mn-butyllithium in hexane (63.9 ml, 102 mmol) under ice-cooling, and themixture was stirred at 35° C. as it was overnight. After the reactionmixture was cooled to −78° C., 1,2-dibromotetrafluoroethane (24.2 g,93.0 mmol) was added, and the mixture was warmed to room temperaturewith stirring. The mixture was stirred at room temperature for 2 hrs.The reaction solution was poured into water, and extracted twice withethyl acetate. The recovered organic layer was dried over anhydrousmagnesium sulfate and the solvent was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=15/1) to give the objectivesubstance.

yellow solid yield 6.439 g, 54%

Recrystallization from hexane gave white crystals.

mp 74-75° C.; ¹H-NMR (CDCl₃, 200 MHz) δ 1.25-1.44 (1H, m), 1.57-2.23(6H, m), 2.26 (3H, s), 2.88 (1H, ddd, J=1.7 Hz, 6.8 Hz, 14.3 Hz), 3.26(1H, dt, J=1.8 Hz, 13.0 Hz), 5.65-5.71 (1H, m), 6.90 (1H, d, J=8.2 Hz),7.26 (1H, d, J=8.0 Hz); IR (KBr) 3326, 2930, 1456, 1090, 1049, 995, 930,856, 806 cm⁻¹; Anal. Calcd for C₁₂H₁₅BrO: C, 56.49; H, 5.93. Found: C,56.48; H, 5.83.

7) 1-bromo-4-methyl-6,7-dihydro-5H-benzo[a]cycloheptene

A solution of4-bromo-1-methyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol (6.213g, 24.35 mmol) and p-toluenesulfonic acid monohydrate (0.46 g, 2.44mmol) in toluene (100 ml) was heated under reflux in a reaction vesselequipped with a Dean-Stark trap under dehydrating conditions for 0.5 hr.After the reaction solution was cooled to room temperature, the solventwas evaporated under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (hexane) to give theobjective substance.

colorless liquid yield 2.485 g, 43% ¹H-NMR (CDCl₃, 300 MHz) δ 1.99-2.13(4H, m), 2.31 (3H, s), 2.6.4 (2H, t, J=6.3 Hz), 6.22 (1H, td, J=6.2 Hz,11.2 Hz), 6.71 (1H, d, J=11.1 Hz), 6.90 (1H, d, J=8.1 Hz), 7.31 (1H, d,J=8.1 Hz); IR (neat) 2930, 1451, 1127, 802, 779 cm⁻¹

8) 4-methyl-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid

To a solution of 1-bromo-4-methyl-6,7-dihydro-5H-benzo[a]cycloheptene(2.485 g, 10.48 mmol) in diethyl ether (30 ml) was dropwise added asolution of 1.6 M n-butyllithium in hexane (9.82 ml, 15.7 mmol) at −78°C., and the mixture was stirred at room temperature for 4 hrs. After thereaction mixture was cooled to −78° C., pulverized dry ice (5 g) wasadded, and the mixture was warmed to room temperature with stirring. Thereaction solution was diluted with water and washed with diethyl ether.The obtained aqueous solution was acidified with 1N hydrochloric acid,and extracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous magnesium sulfate and the solvent was evaporatedunder reduced pressure. The obtained crude crystals were washed withhexane to give the objective substance.

white crystal yield 1.080 g, 51%. mp 152-153° C.; ¹H-NMR (CDCl₃, 200MHz) δ 1.91-2.18 (4H, m), 2.43 (3H, s), 2.66 (2H, t, J=6.6 Hz), 6.26(1H, td, J=6.6 Hz, 11.0 Hz), 7.13 (1H, d, J=7.8 Hz), 7.21 (1H, d, J=11.0Hz), 7.85 (1H, d, J=8.2 Hz); IR (KBr) 3044-2510, 1686, 1300, 1271, 1258cm⁻¹; Anal. Calcd for C₁₃H₁₄O₂: C, 77.20; H, 6.98. Found: C, 76.98; H,7.03.

9)N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-4-methyl-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(0.366 g, 1.013 mmol),4-methyl-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (0.20 g,1.01 mmol) and 1-hydroxybenzotriazole hydrate (0.16 g, 1.01 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.19 g, 1.01 mmol) was added, and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solution,dried over anhydrous magnesium sulfate and passed through silica gel.The solvent was evaporated under reduced pressure. The obtained residuewas crystallized from ethyl acetate-diisopropyl ether-hexane to give theobjective substance.

white crystal yield 0.461 g yield 83% mp 177-178° C.; ¹H-NMR (CDCl₃, 300MHz) δ 1.95-2.07 (4H, m), 2.33 (3H, s), 2.59 (2H, t, J=5.7 Hz), 2.78(1H, dd, J=10.7 Hz, 14.6 Hz), 2.98 (1H, dd, J=4.2 Hz, 14.4 Hz), 3.90(1H; d, J=3.9 Hz), 4.58-4.67 (1H, m), 5.03 (1H, t, J=3.6 Hz), 5.74 (1H,d, J=7.5 Hz), 5.89 (1H, tt, J=2.8 Hz, 53.0 Hz), 6.02 (1H, td, J=6.2 Hz,11.3 Hz), 6.29 (1H, d, J=11.1 Hz), 6.96-7.11 (7H, m), 7.29 (1H, t, J=7.8Hz), 7.42 (2H, dd, J=5.4 Hz, 8.7 Hz); IR (KBr) 3279, 1638, 1512, 1200,1127 cm⁻¹; Anal. Calcd for C₃₀H₂₈F₅NO₃: C, 66.05; H, 5.17; N, 2.57.Found: C, 66.03; H, 5.21; N, 2.52.

Example 319 tert-butylN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[[3-(1,1,2,2-tetrafluoroethoxy)isooxazol-5-yl]methyl]ethyl]carbamate

1) ethyl3-(4-fluorophenyl)-3-oxo-2-[[3-(1,1,2,2-tetrafluoroethoxy)isoxazol-5-yl]methyl]propionate

To a solution of methyl 3-(1,1,2,2-tetrafluoroethoxy)-5-isoxazolecarboxylate (1.975 g, 8.124 mmol) in methanol (30 ml) was added sodiumborohydride (0.40 g, 10.6 mmol) by small portions under ice-cooling, andthe mixture was stirred overnight at room temperature. To the reactionsolution was added dilute hydrochloric acid, the mixture was stirred atroom temperature for 1 hr and washed three times with ethyl acetate. Therecovered organic layer was dried over anhydrous magnesium sulfate, andpassed through silica gel. The solvent was evaporated under reducedpressure to give a crude product of[3-(1,1,2,2-tetrafluoroethoxy)isoxazol-5-yl]methanol as a yellow liquid(1.72 g).

To a solution of the liquid obtained above and triethylamine (1.70 ml,12.2 mmol) in ethyl acetate (40 ml) was dropwise added methanesulfonylchloride (0.75 ml, 9.75 mmol) under ice-cooling, and the mixture wasstirred as it was for 10 min. The resulting precipitate was removed byfiltration, and the precipitate was washed with ethyl acetate. Thesolvent of the recovered filtrate was evaporated under reduced pressureto give a crude product of methanesulfonic acid ester as a yellowliquid.

To a solution of ethyl (4-fluorobenzoyl)acetate (1.88 g, 8.94 mmol) in1,2-dimethoxyethane (30 ml) was added a suspension (0.36 g, 8.94 mmol)of 60% sodium hydride in liquid paraffin under ice-cooling, and themixture was stirred as it was for 0.5 hr. A solution of methanesulfonicacid ester obtained above in 1,2-dimethoxyethane (10 ml) was added atroom temperature, and the mixture was stirred at 70° C. for 4 hrs. Thereaction solution was poured into water, and extracted twice with ethylacetate. The recovered organic layer was dried over anhydrous magnesiumsulfate and the solvent was evaporated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(hexane/ethyl acetate=9/1-6/1) to give the objective substance.

pale-yellow liquid yield 2.418 g, 73% ¹H-NMR (CDCl₃, 200 MHz) δ 1.16(3H, t, J=7.2 Hz), 3.46 (2H, d, J=7.4 Hz), 4.16 (2H, q, J=7.1 Hz), 4.77(1H, t, J=7.4 Hz), 6.00 (1H, tt, J=3.3 Hz, 52.7 Hz), 6.07 (1H, s), 7.18(2H, t, J=8.7 Hz), 8.06 (2H, dd, J=5.3 Hz, 8.9 Hz); IR (neat) 1738,1690, 1601, 1447, 1283, 1233, 1182, 1159 cm⁻¹

2) ethyl(2RS,3SR)-3-(4-fluorophenyl)-3-hydroxy-2-[[3-(1,1,2,2-tetrafluoroethoxy)isoxazol-5-yl]methyl]propionate

While stirring zinc chloride (6.35 g, 46.6 mmol) in diethyl ether (100ml), sodium borohydride (3.53 g, 93.2 mmol) was added at roomtemperature, and the mixture was stirred as it was for 2 hrs. Theinsoluble material of the mixture was removed by filtration and washedwith diethyl ether to give a solution of zinc borohydride in diethylether. A solution of ethyl3-(4-fluorophenyl)-3-oxo-2-[[3-(1,1,2,2-tetrafluoroethoxy)isoxazol-5-yl]methyl]propionate(2.372 g, 5.824 mmol) in diethyl ether (30 ml) was added to the obtainedsolution under ice-cooling, and the mixture was heated under reflux for4 hrs. To the reaction solution was added dilute hydrochloric acid bysmall portions to decompose excess zinc borohydride, and the mixture wasextracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous magnesium sulfate and the solvent was evaporatedunder reduced pressure. The obtained crude product was purified bysilica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to givethe objective substance.

colorless liquid yield 1.402 g, 59% ¹H-NMR (CDCl₃, 300 MHz) δ 1.11 (3H,t, J=7.1 Hz), 2.72 (1H, d, J=3.0 Hz), 2.98-3.26 (3H, m), 4.02-4.11 (2H,m), 5.11 (1H, dd, J=3.3 Hz, 5.1 Hz), 5.93 (1H, s), 6.00 (1H, tt, J=3.3Hz, 52.7 Hz), 7.06 (2H, t, J=8.7 Hz), 7.36 (2H, dd, J=5.3 Hz, 8.6 Hz);IR (neat) 3465, 1728, 1609, 1512, 1449, 1225, 1184, 1146 cm⁻¹

3)(4RS,5SR)-5-(4-fluorophenyl)-4-[[3-(1,1,2,2-tetrafluoroethoxy)isoxazol-5-yl]methyl]-1,3-oxazolidin-2-one

To a solution of ethyl(2RS,3SR)-3-(4-fluorophenyl)-3-hydroxy-2-[[3-(1,1,2,2-tetrafluoroethoxy)isoxazol-5-yl]methyl]propionate(1.402 g, 3.425 mmol) in methanol (30 ml) was added 1N aqueous sodiumhydroxide solution (6.85 ml, 6.85 mmol), and the mixture was stirred atroom temperature for 2 hrs. The reaction solution was concentrated anddiluted with water. The reaction solution was acidified with 1Nhydrochloric acid, and extracted twice with ethyl acetate. The recoveredorganic layer was dried over anhydrous sodium sulfate and the solventwas evaporated under reduced pressure to give a crude product of(2RS,3SR)-3-(4-fluorophenyl)-3-hydroxy-2-[[3-(1,1,2,2-tetrafluoroethoxy)isoxazol-5-yl]methyl]propionicacid as a colorless liquid.

To a solution of the liquid obtained above in tetrahydrofuran (30 ml)were added triethylamine (0.57 ml, 4.11 mmol) and diphenylphosphorylazide (1.04 g, 3.77 mmol), and the mixture was stirred at 70° C.overnight. The solvent of the reaction solution was evaporated underreduced pressure, and the obtained crude product was purified by silicagel column chromatography (hexane/ethyl acetate=3/1-1/1).Crystallization from diethyl ether-hexane gave the objective substance.

white crystal yield 0.921 g, 71% mp 124-125° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 2.48 (1H, dd, J=5.3 Hz, 15.5 Hz), 2.59 (1H, dd, J=8.4 Hz, 15.6 Hz),4.45-4.53 (1H, m), 5.52 (1H, br s), 5.83 (1H, s), 6.00 (1H, tt, J=3.2Hz, 52.7 Hz), 7.12 (2H, t, J=8.6 Hz), 7.32 (2H, dd, J=5.3 Hz, 8.3 Hz);IR (KBr) 3156, 1755, 1447, 1235, 1209, 1150, 1119 cm⁻¹; Anal. Calcd forC₁₅H₁₁F₅N₂O₄: C, 47.63; H, 2.93; N, 7.41. Found: C, 47.60; H, 2.98; N,7.21.

4) tert-butyl(4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-[[3-(1,1,2,2-tetrafluoroethoxy)isoxazol-5-yl]methyl]-1,3-oxazolidine-3-carboxylate

A solution of(4RS,5SR)-5-(4-fluorophenyl)-4-[[3-(1,1,2,2-tetrafluoroethoxy)isoxazol-5-yl]methyl]-1,3-oxazolidin-2-one(0.866 g, 2.289 mmol), di-tert-butyl dicarbonate (0.60 g, 2.75 mmol) and4-N,N-dimethylaminopyridine (28 mg, 0.23 mmol) in acetonitrile (10 ml)was stirred overnight at room temperature. The solvent of the reactionsolution was evaporated under reduced pressure, and the obtained crudeproduct was purified by silica gel column chromatography (ethylacetate). Crystallization from ethyl acetate-diisopropyl ether-hexanegave the objective substance.

white crystal yield 0.785 g, 72% mp 177-178° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.55 (9H, s), 2.81 (1H, dd, J=9.3 Hz, 15.6 Hz), 3.01 (1H, ddd, J=1.0Hz, 4.6 Hz, 15.4 Hz), 4.96-5.03 (1H, m), 5.36 (1H, s), 5.72 (1H, d,J=7.2 Hz), 5.97 (1H, tt, J=3.3 Hz, 52.8 Hz), 7.04 (2H, t, J=8.6 Hz),7.23 (2H, dd, J=5.3 Hz, 8.6 Hz); IR.(KBr) 1802, 1372, 1298, 1163 cm⁻¹;Anal. Calcd for C₂₀H₁₉F₅N₂O₆: C, 50.22; H, 4.00; N, 5.86. Found: C,50.16; H, 3.79; N, 5.88.

5) tert-butylN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[[3-(1,1,2,2-tetrafluoroethoxy)isoxazol-5-yl]methyl]ethyl]carbamate

To a solution of tert-butyl(4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-[[3-(1,1,2,2-tetrafluoroethoxy)isoxazol-5-yl]methyl]-1,3-oxazolidine-3-carboxylate(0.735 g, 1.536 mmol) in tetrahydrofuran (10 ml) was added a solution ofsodium hydroxide (61 mg; 1.54 mmol) in methanol (2 ml) underice-cooling, and the mixture was stirred at room temperature for 10 min.The reaction solution was diluted with-ethyl acetate, washed with water,dried over anhydrous magnesium sulfate and passed through silica gel.The solvent was evaporated under reduced pressure and the obtainedresidue was crystallized from diisopropyl ether-hexane to give theobjective substance.

white crystal yield 0.626 g 90% mp 114-115° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.39 (9H, s), 2.69 (1H, br d, J=2.7 Hz), 2.86 (1H, dd, J=4.2 Hz, 15.3Hz), 3.01 (1H, dd, J=10.7 Hz, 15.5 Hz), 4.09-4.18 (1H, m), 4.89 (1H, brd, J=7.5 Hz), 4.94 (1H, br s), 6.00 (1H, tt, J=3.4 Hz, 52.7 Hz), 6.03(1H, s), 7.08 (2H, t, J=8.7 Hz), 7.38 (2H, dd, J=5.1 Hz, 8.4 Hz); IR(KBr) 3360, 1680, 1530, 1449, 1190, 1125 cm⁻¹; Anal. Calcd forC₁₉H₂₁F₅N₂O₅: C, 50.45; H, 4.68; N, 6.19. Found: C, 50.32; H, 4.58; N,6.25.

Example 320N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[[3-(1,1,2,2-tetrafluoroethoxy)isoxazol-5-yl]methyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

A solution of tert-butylN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[[3-(1,1,2,2-tetrafluoroethoxy)isoxazol-5-yl]methyl]ethyl]carbamate(0.291 g, 0.643 mmol) and conc. hydrochloric acid. (0.2 ml) in methanol(5 ml) was stirred at 60° C. for 0.5 hr. The reaction solution wasdiluted with water, alkalified with potassium carbonate, and extractedtwice with ethyl acetate. The recovered organic layer was dried overanhydrous sodium sulfate and the solvent was evaporated under reducedpressure to give a crude product of(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)isoxazol-5-yl]propan-1-olas a white solid (0.227 g).

While stirring the solid obtained above,6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (0.13 g, 0.71mmol) and 1-hydroxybenzotriazole hydrate (0.10 g, 0.71 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.14 g, 0.71 mmol) was added, and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solutionand dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure and the obtained residue was purified by silicagel column chromatography (hexane/ethyl acetate=3/1-1/1).Crystallization from diisopropyl ether-hexane gave the objectivesubstance.

white powder yield 0.251 g, 75% mp 127-128° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.98-2.06 (2H, m), 2.20-2.26 (2H, m), 2.67-2.71 (2H, m), 3.01 (1H, dd,J=4.2 Hz, 15.9 Hz), 3.12 (1H, d, J=3.9 Hz), 3.16 (1H, dd, J=10.2 Hz,16.2 Hz), 4.61-4.70 (1H, m), 5.02 (1H, t, J=3.9 Hz), 6.00 (1H, tt, J=3.3Hz, 52.5 Hz), 6.03 (1H, td, J=5.6 Hz, 11.7 Hz), 6.11 (1H, s), 6.15 (1H,d, J=8.7 Hz), 6.33 (1H, d, J=11.7 Hz), 7.05-7.14 (4H, m), 7.16-7.22 (1H,m), 7.42 (2H, dd, J=5.3 Hz, 8.9 Hz); IR (KBr) 3289, 1640, 1514, 1449,1188, 1146 cm⁻¹; Anal. Calcd for C₂₆H₂₃F₅N₂O₄: C, 59.77; H, 4.44; N,5.36. Found: C, 59.82; H, 4.48; N, 5.34.

Example 321N-[(1RS,2SR)-2-[4-[(tert-butoxycarbonyl)amino]phenyl]-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution of4-[(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a]cyclohepten-1-ylcarbonyl)amino]-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl]benzoicacid (3.283 g, 5.888 mmol) in tert-butyl alcohol (60 ml) were addedtriethylamine (1.23 ml, 8.83 mmol) and diphenylphosphoryl azide (1.78 g,6.48 mmol), and the mixture was stirred at 80° C. for 2 days. Thesolvent was evaporated under reduced pressure, and the obtained crudeproduct was purified by silica gel column chromatography(hexane-hexane/ethyl acetate=1/1). Crystallization from diisopropylether-hexane gave the objective substance.

white powder yield 2.714 g, 73% mp 153-156° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.52 (9H, s), 1.95-2.03 (2H, m), 2.16-2.23 (2H, m), 2.66 (2H, t, J=5.7Hz), 2.75 (1H, dd, J=10.5 Hz, 14.4 Hz), 2.99 (1H, dd, J=3.6 Hz, 14.4Hz), 3.57 (1H, d, J=3.6 Hz), 4.65-4.75 (1H, m), 5.00 (1H, t, J=3.6 Hz),5.74 (1H, d, J=8.4 Hz), 5.89 (1H, tt, J=2.9 Hz, 53.0 Hz), 5.91 (1H, td,J=5.6 Hz, 11.4 Hz), 6.22 (1H, d, J=12.0 Hz), 6.52 (1H, s), 6.95-7.16(6H, m), 7.30 (1H, t, J=7.8 Hz), 7.38 (4H, s); IR (KBr) 3314, 1694,1676, 1636, 1532, 1314, 1211, 1161, 1115 cm⁻¹; Anal. Calcd forC₃₄H₃₆F₄N₂O₅, DMF: C, 63.33; H, 6.18; N, 5.99. Found: C, 63.30; H, 6.07;N, 5.84.

Example 322N-[(1RS,2SR)-2-(4-aminophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

A solution ofN-[(1RS,2SR)-2-[4-[(tert-butoxycarbonyl)amino]phenyl]-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(1.547 g, 2.461 mmol) and conc. hydrochloric acid (0.5 ml) in methanol(10 ml) was stirred at 60° C. for 2 hrs. The reaction solution wasdiluted with water, alkalified with potassium carbonate, and extractedtwice with ethyl acetate. The recovered organic layer was dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure and the obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate=1/1-1/3). Crystallization fromdiisopropyl ether-hexane gave the objective substance.

pale-brown powder yield 0.150 g, 12%. mp 153-155° C.; ¹H-NMR (CDCl₃, 300MHz) δ 1.94-2.03 (2H, m), 2.15-2.23 (2H, m), 2.66 (2H, t, J=5.9 Hz),2.77 (1H, dd, J=10.2 Hz, 14.7 Hz), 3.03 (1H, dd, J=4.2 Hz, 14.4 Hz),3.19 (1H, d, J=3.9 Hz), 3.70 (2H, br s), 4.65-4.74 (1H, m), 4.90 (1H, t,J=3.8 Hz), 5.71 (1H, d, J=8.4 Hz), 5.89 (1H, tt, J=2.9 Hz, 53.1 Hz),5.91 (1H, td, J=5.3 Hz, 11.7 Hz), 6.20 (1H, d, J=11.7 Hz), 6.69 (2H, d,J=8.1 Hz), 6.97 (1H, dd, J=1.4 Hz, 7.7 Hz), 7.03-7.15 (5H, m), 7.21-7.32(3H, m); IR (KBr) 3270, 1642, 1518, 1275, 1198, 1125 cm⁻¹; Anal. Calcdfor C₂₉H₂₈F₄N₂O₃: C, 65.90; H, 5.34; N, 5.30. Found: C, 65.68; H, 5.15;N, 5.02.

Example 323N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-(3-isopropylbenzyl)ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1) 3-isopropylbenzyl alcohol

While stirring a solution of powdery magnesium (3.33 g, 137 mmol) andiodine (one crumb) in tetrahydrofuran (10 ml), a solution of3-isopropylbromobenzene (10.91 g, 54.80 mmol) and 1,2-dibromoethane(10.3 g, 54.8 mmol) in tetrahydrofuran (100 ml) was dropwise addedslowly. After completion of the dropwise addition, the mixture wasstirred at 70° C. for 1 hr. The reaction solution was cooled to −78° C.,and pulverized dry ice (10 g) was carefully added. The reaction solutionwas gradually warmed to room temperature with stirring. The reactionsolution was diluted with water, acidified with conc. hydrochloric acid,and extracted twice with ethyl acetate. The solvent of the recoveredorganic layer was evaporated under reduced pressure to give a crudeproduct of 3-isopropylbenzoic acid as a yellow liquid.

To a suspension of lithium aluminum hydride (3.12 g, 82.2 mmol) intetrahydrofuran (100 ml) was dropwise added a solution of the liquidobtained above in tetrahydrofuran (50 ml) under ice-cooling, and themixture was stirred at room temperature for 1 hr. After ice-cooling thereaction solution, water (3 ml), 15% aqueous sodium hydroxide solution(3 ml) and water (7.5 ml) were successively added dropwise to decomposeexcess lithium aluminum hydride. The mixture was stirred as it was atroom temperature for 1 hr. The resulting precipitate was removed byfiltration and washed with ethyl acetate. The solvent of the recoveredfiltrate was evaporated under reduced pressure and the obtained residuewas purified by silica gel column chromatography (hexane/ethylacetate=6/1−3/1) to give the objective substance.

yellow liquid yield 5.610 g, 68% ¹H-NMR (CDCl₃, 200 MHz) δ 1.26 (6H, d,J=7.0 Hz), 1.64 (1H, t, J=5.9 Hz), 2.85-2.99 (1H, m), 4.68 (2H, d, J=5.6Hz), 7.15-7.34 (4H, m); IR (neat) 3320, 2961, 1464, 1017, 791, 704 cm⁻¹

2) ethyl 3-(4-fluorophenyl)-2-(3-isopropylbenzyl)-3-oxopropionate

To a solution of 3-isopropylbenzyl alcohol (2.595 g, 17.27 mmol) andtriethylamine (3.61 ml, 25.9 mmol) in ethyl acetate (30 ml) was dropwiseadded a solution of methanesulfonyl chloride (2.37 g, 20.7 mmol) inethyl acetate (10 ml) under ice-cooling, and the mixture was stirred asit was for 10 min. The resulting precipitate was removed by filtrationand washed with ethyl acetate. The solvent of the recovered filtrate wasevaporated under reduced pressure to give a crude product ofmethanesulfonic acid ester as a yellow liquid.

To a solution of ethyl (4-fluorobenzoyl)acetate (3.63 g, 17.3 mmol) in1,2-dimethoxyethane (30 ml) was added a suspension (0.69 g, 17.3 mmol)of 60% sodium hydride in liquid paraffin under ice-cooling, and themixture was stirred as it was for 0.5 hr. A solution of methanesulfonicacid ester obtained above in 1,2-dimethoxyethane (10 ml) was added atroom temperature, and the mixture was stirred at 60° C. overnight. Thereaction solution was poured into water, and extracted twice with ethylacetate. The recovered organic layer was dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theobtained residue was purified by silica gel column chromatography(hexane/ethyl acetate=9/1-6/1) to give the objective substance.

pale-yellow liquid yield 5.108 g, 86% ¹H-NMR (CDCl₃, 200 MHz) δ 1.13(3H, t, J=7.2 Hz), 1.18 (6H, d, J=7.0 Hz), 2.76-2.90 (1H, m), 3.30 (1H,d, J=7.4 Hz), 3.31 (1H, d, J=7.4 Hz), 4.11 (2H, q, J=7.1 Hz), 4.57 (1H,t, J=7.3 Hz), 7.00-7.22 (6H, m), 7.96 (2H, dd, J=5.4 Hz, 9.0 Hz); IR(neat) 2961, 1738, 1688, 1599, 1507, 1271, 1233, 1159 cm⁻¹

3) ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(3-isopropylbenzyl)propionate

While stirring zinc chloride (3.99 g, 29.3 mmol) in diethyl ether (30ml), sodium borohydride (2.22 g, 58.6 mmol) was added at roomtemperature, and the mixture was stirred as it was for 2 hrs. Theinsoluble material in the mixture was removed by filtration and washedwith diethyl ether to give a solution of zinc borohydride in diethylether. To the obtained solution was added a solution of ethyl3-(4-fluorophenyl)-2-(3-isopropylbenzyl)-3-oxopropionate (5.016 g, 14.65mmol) in diethyl ether (30 ml) under ice-cooling, and the mixture wasstirred at 0° C. for 20 min. To the reaction solution was added dilutehydrochloric acid by small portions to decompose excess zincborohydride, and the mixture was extracted twice with ethyl acetate. Therecovered organic layer was dried over anhydrous magnesium sulfate andthe solvent was evaporated under reduced pressure. The obtained crudeproduct was purified by silica gel column chromatography (hexane/ethylacetate=6/1−3/1) to give the objective substance.

colorless liquid yield 4.166 g, 83% ¹H-NMR (CDCl₃, 300 MHz) δ 0.91 (3H,t, J=7.2 Hz), 1.20 (6H, d, J=7.2 Hz), 2.78-2.87 (1H, m), 2.91-3.00 (4H,m), 3.87 (2H, q, J=7.2 Hz), 5.01 (1H, t, J=3.3 Hz), 6.89-6.93 (2H, m),7.02-7.08 (3H, m), 7.16 (1H, t, J=7.5 Hz), 7.38 (2H, dd, J=5.7 Hz, 8.7Hz); IR (neat) 3466, 2961, 1726, 1713, 1605, 1510, 1375, 1225, 1179,1157, 1032, 837 cm⁻¹

4) (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(3-isopropylbenzyl)propionicacid

A mixture of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(3-isopropylbenzyl)propionate(4.166 g, 12.10 mmol), sodium hydroxide (0.97 g, 24.2 mmol), methanol(30 ml), water (30 ml) and tetrahydrofuran (30 ml) was stirred at 60° C.for 6 hrs. The reaction solution was concentrated, diluted with water,acidified with 1N hydrochloric acid, and extracted twice with ethylacetate. The recovered organic layer was dried over anhydrous sodiumsulfate and the solvent was evaporated under reduced pressure. Theresidue was crystallized from diisopropyl ether-hexane to give theobjective substance.

white crystal yield 3.208 g, 84% mp 102-104° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.19 (6H, d, J=6.9 Hz), 2.77-2.86 (1H, m), 2.89-3.07 (3H, m), 5.04(1H, d, J=4.8 Hz), 6.88-6.91 (2H, m), 7.01-7.07 (3H, m), 7.15 (1H, t,J=7.5 Hz), 7.36 (2H, dd, J=5.6 Hz, 8.6 Hz); IR (KBr) 3341, 3100-2550,1694, 1514, 1229, 1020, 837, 785, 702 cm⁻¹; Anal. Calcd for C₁₉H₂₁FO₃:C, 72.13; H, 6.69. Found: C, 72.02; H, 6.64.

5)(4RS,5SR)-5-(4-fluorophenyl)-4-(3-isopropylbenzyl)-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(3-isopropylbenzyl)propionicacid (2.982 g, 9.426 mmol) in tetrahydrofuran (50 ml) were addedtriethylamine (1.58 ml, 11.3 mmol) and diphenylphosphoryl azide (2.85 g,10.4 mmol), and the mixture was stirred at 65° C. overnight. The solventof the reaction solution was evaporated under reduced pressure, and theobtained crude product was purified by silica gel column chromatography(hexane/ethyl acetate=3/1-1/1). Crystallization from diisopropylether-hexane gave the objective substance.

white crystal yield 2.680 g, 91% mp 153-154° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.21 (6H, d, J=6.9 Hz), 2.19 (1H, dd, J=10.8 Hz, 13.8 Hz), 2.28 (1H,dd, J=4.1 Hz, 13.7 Hz), 2.77-2.91 (1H, m), 4.24 (1H, ddd, J=3.7 Hz, 8.2Hz, 11.2 Hz), 4.94 (1H, br s), 5.79 (1H, d, J=8.1 Hz), 6.84-6.87 (2H,m), 7.09-7.24 (4H, m), 7.38 (2H, dd, J=5.3 Hz, 8.6 Hz); IR (KBr) 3306,2969, 1759, 1723, 1701, 1510, 1424, 1225, 1078, 1007 cm⁻¹; Anal. Calcdfor C₁₉H₂₀FNO₂: C, 72.82; H, 6.43; N, 4.47. Found: C, 72.81; H, 6.60; N,4.41.

6) (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-isopropylphenyl)propan-1-ol

(4RS,5SR)-5-(4-fluorophenyl)-4-(3-isopropylbenzyl)-1,3-oxazolidin-2-one(2.453 g, 7.828 mmol) and sodium hydroxide (1.25 g, 31.3 mmol) wereheated under reflux in ethanol (25 ml)-water (1.5 ml) for 3 hrs. Thereaction solution was diluted with water, and extracted twice with ethylacetate. The recovered organic layer was dried over anhydrous sodiumsulfate, passed through APS-silica gel, and the solvent was evaporatedunder reduced pressure. The residue was crystallized from diisopropylether-hexane to give the objective substance.

white crystal yield 1.999 g, 89% mp 88-90° C.; ¹H-NMR (CDCl₃, 300 MHz) δ1.23 (6H, d, J=6.6 Hz), 2.30 (1H, dd, J=10.4 Hz, 13.4 Hz), 2.77 (1H, dd,J=3.3 Hz, 13.5 Hz), 2.82-2.91 (1H, m), 3.29 (1H, ddd, J=3.3 Hz, 5.0 Hz,10.4 Hz), 4.67 (1H, d, J=5.1 Hz), 6.94-6.98 (2H, m), 7.05-7.11 (3H, m),7.22 (1H, t, J=7.4 Hz), 7.38 (2H, dd, J=5.6 Hz, 8.6 Hz); IR (KBr)3150-2780, 1508, 1215, 1046, 980, 818, 710 cm⁻¹; Anal. Calcd forC₁₈H₂₂FNO: C, 75.23; H, 7.72; N, 4.87. Found: C, 75.33; H, 7.82; N,4.78.

7)N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-(3-isopropylbenzyl)ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-isopropylphenyl)propan-1-ol(0.250 g, 0.870 mmol), 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylicacid (0.16 g, 0.87 mmol) and 1-hydroxybenzotriazole hydrate (0.13 g,0.87 mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 g,0.87 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white crystal yield 0.330 g, 83% mp 165-167° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.20 (6H, d, J=6.9 Hz), 1.94-2.03 (2H, m), 2.14-2.22 (2H, m), 2.66(2H, t, J=5.9 Hz), 2.68 (1H, dd, J=11.1 Hz, 14.1 Hz), 2.80-2.89 (1H, m),2.99 (1H, dd, J=4.5 Hz, 14.1 Hz), 4.18 (1H, d, J=3.9 Hz), 4.64-4.73 (1H,m), 5.02 (1H, t, J=3.6 Hz), 5.65 (1H, d, J=7.5 Hz), 5.91 (1H, td, J=5.6Hz, 11.2 Hz), 6.24 (1H, d, J=11.7 Hz), 6.89 (1H, dd, J=0.9 Hz, 7.2 Hz),6.98-7.15 (7H, m), 7.22 (1H, t, J=8.0 Hz), 7.43 (2H, dd, J=5.4 Hz, 8.7Hz); IR (KBr) 3281, 2961, 2942, 1640, 1510, 1225, 833, 704 cm⁻¹; Anal.Calcd for C₃₀H₃₂FNO₂: C, 78.75; H, 7.05; N, 3.06. Found: C, 78.66; H,7.15; N, 2.98.

Example 3244-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-(3-isopropylbenzyl)ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-isopropylphenyl)propan-1-ol(0.250 g, 0.870 mmol), 4-fluoro-1-naphthoic acid (0.17 g, 0.87 mmol) and1-hydroxybenzotriazole hydrate (0.13 g, 0.87 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17g, 0.87 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white crystal yield 0.355 g, 89% mp 159-160° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.18 (3H, d, J=7.2 Hz), 1.19 (3H, d, J=7.2 Hz), 2.73 (1H, dd, J=11.1Hz, 14.4 Hz), 2.80-2.89 (1H, m), 3.06 (1H, dd, J=4.2 Hz, 14.4 Hz), 4.02(1H, d, J=4.2 Hz), 4.74-4.83 (1H, m), 5.08 (1H, t, J=3.9 Hz), 5.81 (1H,d, J=7.8 Hz), 6.96 (1H, dd, J=8.1 Hz, 9.9 Hz), 7.01-7.15 (6H, m), 7.25(1H, t, J=7.5 Hz), 7.42-7.47 (3H, m), 7.54 (1H, t, J=8.1 Hz), 7.80 (1H,d, J=8.4 Hz), 8.07 (1H, d, J=8.4 Hz); IR (KBr) 3272, 2965, 1640, 1626,1601, 1539, 1512, 1329, 1264, 1229, 1051, 833, 760 cm⁻¹; Anal. Calcd forC₂₉H₂₇F₂NO₂.0.1H₂O: C, 75.50; H, 5.94; N, 3.04. Found: C, 75.24; H,5.94; N, 3.44.

Example 325 tert-butylN-[(1RS,2SR)-2-(4-formylphenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]carbamate

1)(4RS,5SR)-5-[4-(hydroxymethyl)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one

A solution of(4RS,5SR)-5-[4-(methoxycarbonyl)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one(1.518 g, 3.552 mmol) and sodium borohydride (1.34 g, 35.5 mmol) inmethanol (3 ml)-tetrahydrofuran (50 ml) was heated under reflux for 6hrs. After cooling the reaction solution to room temperature, dilutehydrochloric acid was added by small portions at room temperature andthe mixture was stirred for 0.5 hr, and extracted twice with ethylacetate. The recovered organic layer was dried over anhydrous magnesiumsulfate and the solvent was evaporated under reduced pressure. Theobtained crude product was purified by silica gel column chromatography(hexane/ethyl acetate=1/1-1/2). Crystallization from diisopropylether-hexane gave the objective substance.

white crystal yield 0.899 g, 63% mp 124-125° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.75 (1H, t, J=5.9 Hz), 2.26 (1H, dd, J=10.2 Hz, 13.8 Hz), 2.33 (1H,dd, J=4.5 Hz, 13.8 Hz), 4.22-4.29 (1H, m), 4.75 (2H, d, J=6.0 Hz), 4.94(1H, br s), 5.83 (1H, d, J=8.1 Hz), 5.90 (1H, tt, J=2.8 Hz, 53.0 Hz),6.85 (1H, s), 6.96 (1H, d, J=7.8 Hz), 7.10 (1H, dd, J=1.1 Hz, 8.3 Hz),7.31 (1H, t, J=8.0 Hz), 7.37 (2H, d, J=8.1 Hz), 7.45 (2H, d, J=8.4 Hz);IR (KBr) 3243, 1746, 1208, 1123 cm⁻¹; Anal. Calcd for C₁₉H₁₇F₄NO₄: C,57.15; H, 4.29; N, 3.51. Found: C, 56.95; H, 4.05; N, 3.40.

2)4-[(4RS,5SR)-2-oxo-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-5-yl]benzaldehyde

To a solution of oxalyl chloride (5.58 g, 44.0 mmol) in tetrahydrofuran(100 ml) was dropwise added a solution of dimethyl sulfoxide (6.24 ml,88.0 mmol) in tetrahydrofuran (30 ml) was dropwise added at −78° C. andthe mixture was stirred for 5 min. A solution of(4RS,5SR)-5-[4-(hydroxymethyl)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one(11.71 g, 29.32 mmol) in tetrahydrofuran (50 ml)-dichloromethane (70ml)-dimethyl sulfoxide (30 ml) was added at −78° C., and the mixture wasstirred for 15 min. Triethylamine (24.5 ml, 176 mmol) was added thereto,and the mixture was warmed to room temperature. The reaction mixture waspoured into water, and extracted twice with ethyl acetate. The recoveredorganic layer was dried over anhydrous magnesium sulfate and passedthrough silica gel. The solvent was evaporated under reduced pressureand the obtained crude product was crystallized from diisopropylether-hexane to give the objective substance.

pale-yellow crystal yield 11.39 g, 98% mp 132-133° C.; ¹H-NMR (CDCl₃,300 MHz) δ 2.26 (1H, dd, J=9.9 Hz, 13.5 Hz), 2.33 (1H, dd, J=4.8 Hz,13.8 Hz), 4.30-4.37 (1H, m), 5.10 (1H, br s), 5.89 (1H, d, J=8.1 Hz),5.89 (1H, tt, J=2.8 Hz, 53.1 Hz), 6.85 (1H, s), 6.94 (1H, d, J=7.8 Hz),7.11 (1H, dd, J=1.2 Hz, 8.1 Hz), 7.30 (1H, t, J=8.0 Hz), 7.57 (2H, d,J=7.8 Hz), 7.96 (2H, d, J=8.4 Hz), 10.06 (1H, s); IR (KBr) 3243, 3144,1742, 1703, 1238, 1198, 1144, 1121, 1090 cm⁻¹; Anal. Calcd forC₁₉H₁₅F₄NO₄: C, 57.44; H, 3.81; N, 3.53. Found: C, 57.28; H, 3.87; N,3.39.

3) tert-butyl(4RS,5SR)-5-(4-formylphenyl)-2-oxo-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate

A solution of4-[(4RS,5SR)-2-oxo-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-5-yl]benzaldehyde(11.29 g, 28.41 mmol), di-tert-butyl dicarbonate (7.44 g, 34.1 mmol) and4-N,N-dimethylaminopyridine (0.35 g, 2.84 mmol) in acetonitrile (50 ml)was stirred overnight at room temperature. The solvent of the reactionsolution was evaporated under reduced pressure, and the obtained residuewas purified by silica gel column chromatography (hexane/ethylacetate=3/1-2/1). Crystallization from ethyl acetate-diisopropylether-hexane gave the objective substance.

white crystal yield 12.38 g, 88% mp 143-144° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.53 (9H, s), 2.59 (1H, dd, J=8.9 Hz, 14.6 Hz), 2.94 (1H, dd, J=4.4Hz, 14.3 Hz), 4.85-4.91 (1H, m), 5.75 (1H, d, J=6.9 Hz), 5.84 (1H, tt,J=2.9 Hz, 53.1 Hz), 6.37 (1H, s), 6.60 (1H, d, J=7.8 Hz), 6.94 (1H, dd,J=1.4 Hz, 8.0 Hz), 7.05 (1H, t, J=8.0 Hz)., 7.34 (2H, d, J=8.1 Hz), 7.77(2H, d, J=8.7 Hz), 9.99 (1H, s); IR (KBr) 1804, 1690, 1364, 1348, 1304,1196, 1155, 1121, 1092, 1061 cm⁻¹; Anal. Calcd for C₂₄H₂₃F₄NO₆: C,57.95; H, 4.66; N, 2.82. Found: C, 57.88; H, 4.49; N, 2.71.

4) tert-butylN-[(1RS,2SR)-2-(4-formylphenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]carbamate

To a solution of tert-butyl(4RS,5SR)-5-(4-formylphenyl)-2-oxo-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate(12.20 g, 24.53 mmol) in methanol (20 ml)-tetrahydrofuran (50 ml) wasadded a solution of sodium hydroxide (1.03 g, 25.8 mmol) in methanol (15ml) under ice-cooling, and the mixture was stirred at room temperaturefor 1 hr. The reaction solution was diluted with ethyl acetate, washedwith water, dried over anhydrous magnesium sulfate and passed-throughsilica gel. The solvent was evaporated under reduced pressure and theobtained residue was crystallized from ethyl acetate-diisopropylether-hexane to give the objective substance.

white crystal yield 8.681 g, 75% mp 140-142° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.36 (9H, s), 2.75 (2H, d, J=7.5 Hz), 3.54 (1H, br s), 4.04-4.13 (1H,m), 4.63 (1H, br d, J=8.1 Hz), 5.06 (1H, br s), 5.89 (1H, tt, J=2.9 Hz,53.0 Hz), 6.94 (1H, s), 7.00 (1H, d, J=7.8 Hz), 7.06 (1H, dd, J=1.4 Hz,8.3 Hz), 7.26 (1H, t, J=8.0 Hz), 7.59 (2H, d, J=8.4 Hz), 7.90 (2H, d,J=8.1 Hz), 10.03 (1H, s); IR (KBr) 3358, 1684, 1530, 1277, 1211, 1169,1125 cm⁻¹; Anal. Calcd for C₂₃H₂₅F₄NO₅.0.5H₂O: C, 57.50; H, 5.45; N,2.92. Found: C, 57.33; H, 5.27; N, 2.89.

Example 326N-[(1RS,2SR)-2-(4-formylphenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

A solution of tert-butylN-[(1RS,2SR)-2-(4-formylphenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]carbamate(8.465 g, 17.96 mmol) and trifluoroacetic acid (20 ml) intetrahydrofuran (20 ml) was stirred at 50° C. for 0.5 hr. The reactionsolution was evaporated under reduced pressure, diluted with water,alkalified with potassium carbonate, and extracted twice with ethylacetate. The recovered organic layer was dried over anhydrous sodiumsulfate and the solvent was evaporated under reduced pressure to give abrown liquid.

While stirring the liquid obtained above,6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (3.38 g, 18.0mmol) and 1-hydroxybenzotriazole hydrate (2.75 g, 18.0 mmol) inacetonitrile, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (3.44 g, 18.0 mmol) was added, and the mixture was stirredat room temperature for 3 days. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solutionand dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure and the obtained residue was purified by silicagel column chromatography (hexane/ethyl acetate=2/1-3/2).Crystallization from ethyl acetate-diisopropyl ether-hexane gave theobjective substance.

white crystal yield 4.388 g, 45% mp 164-166° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.96-2.04 (2H, m), 2.15-2.22 (2H, m), 2.66 (2H, t, J=6.0 Hz), 2.82(1H, dd, J=10.8 Hz, 14.4 Hz), 2.96 (1H, dd, J=4.4 Hz, 14.6 Hz), 3.96(1H, d, J=3.9 Hz), 4.65-4.74 (1H, m), 5.18 (1H, t, J=3.8 Hz), 5.82 (1H,d, J=7.8 Hz), 5.88 (1H, tt, J=2.7 Hz, 53.0 Hz), 5.93 (1H, td, J=5.7 Hz,11.4 Hz), 6.23 (1H, d, J=11.7 Hz), 6.97-7.11 (5H, m), 7.17 (1H, d, J=7.2Hz), 7.30 (1H, t, J=8.1 Hz), 7.66 (2H, d, J=8.4 Hz), 7.91 (2H, d, J=8.1Hz), 10.03 (1H, s); IR (KBr) 3503, 3252, 1694, 1636, 1537, 1285, 1190,1107, 775 cm⁻¹; Anal. Calcd for C₃₀H₂₇F₄NO₄: C, 66.54; H, 5.03; N, 2.59.Found: C, 66.20; H, 5.00; N, 2.32.

Example 327

A solution ofN-[(1RS,2SR)-2-(4-formylphenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.300 g, 0.554 mmol), piperidine (0.11 ml, 1.1 mmol) and acetic acid(0.06 ml, 1.1 mmol) in methanol (10 ml) was stirred at room temperaturefor 1 hr. The sodium cyanoborohydride (70 mg, 1.1 mmol) was added atroom temperature, and the mixture was stirred overnight at roomtemperature. The reaction mixture was poured into aqueous sodiumhydrogen carbonate solution and extracted twice with ethyl acetate. Therecovered organic layer was dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the obtained residuewas purified by silica gel column chromatography (hexane/ethylacetate=3:2-chloroform/methanol=20/1). Precipitation from hexane gavethree kinds of products.

N-[(1RS,2SR)-2-hydroxy-2-[4-(piperidinomethyl)phenyl]-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

white powder yield 0.127 g, 38% mp 104-106° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.40-1.46 (2H, m), 1.53-1.60 (4H, m), 1.94-2.02 (2H, m), 2.15-2.22(2H, m), 2.37 (4H, br s), 2.65 (2H, t, J=5.6 Hz), 2.79 (1H, dd, J=10.7Hz, 14.9 Hz), 3.00 (1H, dd, J=4.5 Hz, 14.7 Hz), 3.46 (2H, s), 3.67 (1H,br s), 4.68-4.75 (1H, m), 5.01 (1H, d, J=3.6 Hz), 5.81. (1H, d, J=8.4Hz), 5.88 (1H, tt, J=2.7 Hz, 53.1 Hz), 5.90 (1H, td, J=5.1 Hz, 12.3 Hz),6.19 (1H, d, J=12.0 Hz), 6.95 (1H, dd, J=1.2 Hz, 7.8 Hz), 7.01-7.15 (5H,m), 7.26-7.33 (3H, m), 7.39 (2H, d, J=8.1 Hz); IR (KBr) 3258, 2932,1632, 1535, 1285, 1198, 1113 cm⁻¹; Anal. Calcd for C₃₅H₃₈F₄N₂O₃. 1.0H₂O:C, 66.86; H, 6.41; N, 4.46. Found: C, 66.55; H, 6.35; N, 4.54.

N-[(1RS,2SR)-2-[4-[cyano(piperidino)methyl]phenyl]-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

white powder yield 35 mg) mp 152-154° C.; ¹H-NMR (CDCl₃, 300 MHz) δ1.43-1.67 (6H, m), 1.96-2.04 (2H, m), 2.16-2.22 (2H, m), 2.51 (4H, brs), 2.66 (2H, t, J=5.9 Hz), 2.74-2.84 (1H, m), 2.94-3.02 (1H, m), 3.78(0.5H, d, J=3.9 Hz), 3.81 (0.5H, d, J=4.2 Hz), 4.67-4.74 (1H, m), 4.81(1H, s), 5.06-5.93 (1H, m), 5.79-5.84 (1H, m), 5.88-5.96 (1H, m), 5.89(1H, tt, J=2.9 Hz, 53.0 Hz), 6.17-6.24 (1H, m), 6.94-7.17 (6H, m), 7.29(1H, t, J=7.8 Hz), 7.48 (2H, d, J=8.7 Hz), 7.55 (2H, d, J=8.4 Hz); IR(KBr) 3353, 2940, 1638, 1522, 1202, 1121 cm⁻¹; Anal. Calcd forC₃₆H₃₇F₄N₃O₃: C, 68.02; H, 5.87; N, 6.61. Found: C, 67.81; H, 6.02; N,6.54.

N-[(1RS,2SR)-2-hydroxy-2-[4-(hydroxymethyl)phenyl]-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

white powder yield 41 g) mp 151-152° C.; ¹H-NMR (CDCl₃, 300 MHz) δ 1.75(1H, t, J=5.7 Hz), 1.96-2.04 (2H, m), 2.16-2.22 (2H, m), 2.66 (2H, t,J=5.9 Hz), 2.78 (1H, dd, J=10.8 Hz, 14.7 Hz), 2.99 (1H, dd, J=4.1 Hz,14.6 Hz), 3.61 (1H, d, J=4.2 Hz), 4.68-4.75 (1H, m), 4.71 (2H, d, J=6.0Hz), 5.06 (1H, t, J=3.6 Hz), 5.77 (1H, d, J=8.1 Hz), 5.89 (1H, tt, J=2.9Hz, 53.0 Hz), 5.91 (1H, td, J=5.4 Hz, 11.7 Hz), 6.22 (1H, d, J=11.4 Hz),6.96-7.16 (6H, m), 7.29 (1H, t, J=8.0 Hz), 7.38 (2H, d, J=8.1 Hz), 7.46(2H, d, J=7.8 Hz); IR (KBr) 3270, 2932, 1638, 1522, 1202, 1123 cm⁻¹;Anal. Calcd for C₃₀H₂₉F₄NO₄.0.1H₂O: C, 66.07; H, 5.40; N, 2.57. Found:C, 65.88; H, 5.29; N, 2.47.

Example 328 tert-butylN-[(1RS,2SR)-2-(6-chloropyridin-3-yl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]carbamate

1) ethyl3-(6-chloropyridin-3-yl)-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate

To a solution of 3-(1,1,2,2-tetrafluoroethoxy)benzyl alcohol (10.5 g,46.8 mmol) and triethylamine (7.83 ml, 56.2 mmol) in ethyl acetate (80ml) was dropwise added a solution of methanesulfonyl chloride (5.90 g,51.5 mmol) in ethyl acetate (20 ml) under ice-cooling, and the mixturewas stirred as it was for 10 min. The resulting precipitate was removedby filtration, and the precipitate was washed with diethyl ether. Thesolvent of the recovered filtrate was evaporated under reduced pressureto give a crude product of methanesulfonic acid ester as a yellowliquid.

To a solution of ethyl 3-(6-chloropyridin-3-yl)-3-oxopropionate (10.66g, 46.83 mmol) in 1,2-dimethoxyethane (100 ml) was added a suspension(1.87 g, 46.8 mmol) of 60% sodium hydride in liquid paraffin underice-cooling, and the mixture was stirred as it was for 0.5 hr. Asolution of methanesulfonic acid ester obtained above in1,2-dimethoxyethane (10 ml) was added thereto at room temperature, andthe mixture was stirred at 60° C. overnight. The reaction solution waspoured into water, and extracted twice with ethyl acetate. The recoveredorganic layer was dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the obtained residue waspurified by silica gel column chromatography (hexane/ethylacetate=9/1-6/1) to give the objective substance.

pale-yellow liquid yield 17.22 g, 85% ¹H-NMR (CDCl₃, 300 MHz) δ 1.14(3H, t, J=7.2 Hz), 3.36 (2H, d, J=7.2 Hz), 4.12 (2H, q, J=7.1 Hz), 4.52(1H, t, J=7.4 Hz), 5.89 (1H, t, J=2.8 Hz, 53.2 Hz), 7.05-7.07 (2H, m),7.13 (1H, d, J=7.8 Hz), 7.29 (1H, t, J=8.3 Hz), 7.42 (1H, dd, J=0.8 Hz,8.3 Hz), 8.16 (1H, dd, J=2.6 Hz, 8.3 Hz), 8.92 (1H, dd, J=0.8 Hz, 2.7Hz); IR (neat) 1738, 1694, 1582, 1364, 1302, 1277, 1196, 1113 cm⁻¹

2) ethyl(2RS,3RS)-3-(6-chloropyridin-3-yl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate

While stirring zinc chloride (10.8 g, 79.0 mmol) in diethyl ether (50ml), sodium borohydride (5.98 g, 158 mmol) was added at roomtemperature, and the mixture was stirred as it was for 2 hrs. Theinsoluble material in the mixture was removed by filtration and washedwith diethyl ether to give a solution of zinc borohydride in diethylether. To the obtained solution was added a solution of ethyl3-(6-chloropyridin-3-yl)-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate(17.14 g, 39.51 mmol) in diethyl ether (50 ml) under ice-cooling, andthe mixture was stirred as it was for 20 min. To the reaction solutionwas added dilute hydrochloric acid by small portions to decompose excesszinc borohydride, and the mixture was extracted twice with ethylacetate. The recovered organic layer was dried over anhydrous magnesiumsulfate and the solvent was evaporated under reduced pressure. Theobtained crude product was purified by silica gel column chromatography(hexane/ethyl acetate=3/1-2/1) to give the objective substance.

pale-yellow liquid yield 13.52 g, 79% ¹H-NMR (CDCl₃, 300 MHz) δ 0.97(3H, t, J=7.1 Hz), 2.90-3.07 (3H, m), 3.28 (1H, d, J=3.0 Hz), 3.93 (2H,q, J=7.2 Hz), 5.10 (1H, t, J=3.3 Hz), 5.89 (1H, tt, J=2.8 Hz, 53.2 Hz),6.95 (1H, s), 6.98-7.07 (2H, m), 7.27 (1H, t, J=7.8 Hz), 7.33 (1H, d,J=8.4 Hz), 7.73 (1H, ddd, J=0.5 Hz, 2.5 Hz, 8.3 Hz), 8.39 (1H, dd, J=0.9Hz, 2.1 Hz); IR (neat) 3353, 1728, 1588, 1460, 1375, 1302, 1279, 1198,1119, 1026 cm⁻¹

3)(2RS,3RS)-3-(6-chloropyridin-3-yl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionicacid

A mixture of ethyl(2RS,3RS)-3-(6-chloropyridin-3-yl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate(13.52 g, 31.02 mmol), sodium hydroxide (2.48 g, 62.0 mmol), methanol(50 ml), tetrahydrofuran (20 ml) and water (50 ml) was stirred at roomtemperature for 2 hrs. The reaction solution was concentrated, dilutedwith water, acidified with hydrochloric acid, and extracted twice withethyl acetate. The recovered organic layer was dried over anhydroussodium sulfate and the solvent was evaporated under reduced pressure.The residue was crystallized from diisopropyl ether-hexane to give theobjective substance.

pale-yellow crystal yield 11.32 g, 90% mp 88-91° C.; ¹H-NMR (CDCl₃, 300MHz) δ 2.92-3.11 (3H, m), 5.10 (1H, d, J=4.5 Hz), 5.88 (1H, tt, J=2.9Hz, 53.1 Hz), 6.99-7.10 (3H, m), 7.23 (1H, t, J=7.8 Hz), 7.31 (1H, d,J=8.1 Hz), 7.77 (1H, dd, J=2.4 Hz, 8.4 Hz), 8.34 (1H, d, J=2.4 Hz); IR(KBr) 3364, 2900-2400, 1686, 1590, 1462, 1316, 1279, 1227, 1202, 1113,1082 cm⁻¹; Anal. Calcd for C₁₇H₁₄ClF₄NO₄: C, 50.08; H, 3.46; N, 3.44.Found: C, 50.01; H, 3.53; N, 3.42.

4)(4RS,5SR)-5-(6-chloropyridin-3-yl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-(6-chloropyridin-3-yl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionicacid (10.94 g, 26.83 mmol) in tetrahydrofuran (80 ml) were addedtriethylamine (4.49 ml, 32.2 mmol) and diphenylphosphoryl azide (8.12 g,29.5 mmol), and the mixture was stirred at 65° C. overnight. The solventof the reaction solution was evaporated under reduced pressure and theobtained crude product was purified by silica gel column chromatography(hexane/ethyl acetate=3/1-1/1). Crystallization from diisopropylether-hexane gave the objective substance.

white crystal yield 8.107 g, 75% mp 131-132° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 2.31 (1H, dd, J=10.5 Hz, 13.8 Hz), 2.38 (1H, dd, J=5.1 Hz, 13.8 Hz),4.30-4.38 (1H, m), 5.23 (1H, s), 5.83 (1H, d, J=7.8 Hz), 5.91 (1H, tt,J=2.9 Hz, 53.0 Hz), 6.89 (1H, s), 6.93 (1H, d, J=7.8 Hz), 7.13 (1H, d,J=8.1 Hz), 7.32 (1H, t, J=7.8 Hz), 7.42 (1H, d, J=8.4 Hz), 7.71 (1H, dd,J=2.4 Hz, 8.4 Hz), 8.39 (1H, d, J=2.4 Hz); IR (KBr) 3252, 1740, 1208,1134, 1105, 758 cm⁻¹; Anal. Calcd for C₁₇H₁₃ClF₄N₂O₃: C, 50.45; H, 3.24;N, 6.92. Found: C, 50.41; H, 3.04; N, 6.95.

5) tert-butyl(4RS,5SR)-5-(6-chloropyridin-3-yl)-2-oxo-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate

A solution of(4RS,5SR)-5-(6-chloropyridin-3-yl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one(7.889 g, 19.49 mmol), di-tert-butyl dicarbonate (5.10 g, 23.4 mmol) and4-N,N-dimethylaminopyridine (0.24 g, 1.95 mmol) in acetonitrile (80 ml)was stirred overnight at room temperature. The solvent of the reactionsolution was evaporated under reduced pressure and the obtained residuewas purified by silica gel column chromatography (hexane/ethylacetate=3/1-1/1). Crystallization from diisopropyl ether-hexane gave theobjective substance.

white crystal yield 9.444 g, 96% mp 130-131° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.54 (9H, s), 2.58 (1H, dd, J=9.7 Hz, 14.5 Hz), 3.03 (1H, dd, J=4.2Hz, 14.2 Hz), 4.83-4.93 (1H, m), 5.70 (1H, d, J=7.0 Hz), 5.90 (1H, tt,J=2.6 Hz, 53.0 Hz), 6.52-6.57 (2H, m), 7.01 (1H, br d, J=8.2 Hz), 7.11(1H, d, J=7.2 Hz), 7.19 (1H, d, J=8.4 Hz), 7.39 (1H, dd, J=2.6 Hz, 8.4Hz), 8.19 (1H, d, J=1.8 Hz); IR (KBr) 2988, 1796, 1730, 1366, 1343,1319, 1204, 1154, 1115, 1074, 1024, 845, 760 cm⁻¹; Anal. Calcd forC₂₂H₂₁ClF₄N₂O₅: C, 52.34; H, 4.19; N, 5.55. Found: C, 52.27; H, 4.03; N,5.35.

6) tert-butylN-[(1RS,2SR)-2-(6-chloropyridin-3-yl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]carbamate

To a solution of tert-butyl(4RS,5SR)-5-(6-chloropyridin-3-yl)-2-oxo-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-3-carboxylate(9.144 g, 18.11 mmol) in methanol (10 ml)-tetrahydrofuran (50 ml) wasadded a solution of sodium hydroxide (0.76 g, 19.0 mmol) in methanol (10ml) under ice-cooling, and the mixture was stirred at room temperaturefor 10 min. The reaction solution was diluted with ethyl acetate, washedwith water, dried over anhydrous magnesium sulfate and passed throughsilica gel. The solvent was evaporated under reduced pressure. Theobtained residue was crystallized from ethyl acetate-diisopropylether-hexane to give the objective substance.

white crystal yield 8.441 g, 97% mp 119-121° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.36 (9H, s), 2.70-2.85 (2H, m), 3.86 (1H, br s), 4.00-4.09 (1H, m),4.55 (1H, d, J=8.1 Hz), 4.95 (1H, s), 5.90 (1H, tt, J=2.8 Hz, 53.1 Hz),6.98 (1H, s), 7.03 (1H, d, J=7.8 Hz), 7.08 (1H, d, J=7.8 Hz), 7.26-7.36(2H, m), 7.73 (1H, dd, J=2.3 Hz, 8.0 Hz), 8.39 (1H, d, J=1.8 Hz); IR(KBr) 3378, 3175, 2982, 1682, 1524, 1460, 1196, 1125, 1105 cm⁻¹; Anal.Calcd for C₂₁H₂₃ClF₄N₂O₄: C, 52.67; H, 4.84; N, 5.85. Found: C, 52.95;H, 4.88; N, 5.83.

Example 329N-[(1RS,2SR)-2-(6-chloropyridin-3-yl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1)(1RS,2SR)-2-amino-1-(6-chloropyridin-3-yl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol

A mixture of tert-butylN-[(1RS,2SR)-2-(6-chloropyridin-3-yl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]carbamate(8.196 g, 17.12 mmol) and trifluoroacetic acid (20 ml) was stirred atroom temperature for 1 hr. The reaction solution was evaporated underreduced pressure, diluted with water, alkalified with potassiumcarbonate, and extracted twice with ethyl acetate. The recovered organiclayer was dried over anhydrous sodium sulfate and passed throughAPS-silica gel. The solvent was evaporated under reduced pressure andthe obtained residue was crystallized from diisopropyl ether-hexane togive the objective substance.

white crystal yield 6.118 g, 94% mp 97-98° C.; ¹H-NMR (CDCl₃, 300 MHz) δ2.37 (1H, dd, J=10.4 Hz, 13.7 Hz), 2.70 (1H, dd, J=3.2 Hz, 14.0 Hz),3.34 (1H, ddd, J=3.5 Hz, 4.2 Hz, 10.1 Hz), 3.58 (1H, br s), 4.75 (1H, d,J=4.2 Hz), 5.90 (1H, tt, J=2.9 Hz, 53.1 Hz), 6.98 (1H, s), 7.04 (1H, d,J=7.5 Hz), 7.09 (1H, d, J=8.1 Hz), 7.31 (1H, t, J=7.8 Hz), 7.36 (1H, d,J=8.1 Hz), 7.75 (1H, dd, J=2.6 Hz, 8.3 Hz), 8.40 (1H, d, J=2.4 Hz); IR(KBr) 3358, 3065-2755, 1588, 1568, 1454, 1279, 1202, 1119, 1100, 1047cm⁻¹; Anal. Calcd for C₁₆H₁₅ClF₄N₂O₂: C, 50.74; H, 3.99; N, 7.40. Found:C, 50.60; H, 3.72; N, 7.13.

2)N-[(1RS,2SR)-2-(6-chloropyridin-3-yl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(6-chloropyridin-3-yl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(1.000 g, 2.640 mmol), 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylicacid (0.50 g, 2.64 mmol) and 1-hydroxybenzotriazole hydrate (0.40 g,2.64 mmol) in acetonitrile (20 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.51 g,2.64 mmol). was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white crystal yield 1.311 g, 91% mp 170-172° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.96-2.05 (2H, m), 2.14-2.22 (2H, m), 2.66 (2H, t, J=6.0 Hz), 2.79(1H, dd, J=11.0 Hz, 14.3 Hz), 3.01 (1H, dd, J=4.2 Hz, 14.4 Hz), 4.29(1H, d, J=3.9 Hz), 4.61-4.69 (1H, m), 5.08 (1H, t, J=3.9 Hz), 5.76 (1H,d, J=7.8 Hz), 5.90 (1H, tt, J=2.8. Hz, 53.0 Hz), 5.94 (1H, td, J=5.8 Hz,11.7 Hz), 6.19 (1H, d, J=11.4 Hz), 6.96 (1H, dd, J=1.5 Hz, 7.8 Hz),7.03-7.18 (5H, m), 7.33 (1H, t, J=8.0 Hz), 7.35 (1H, d, J=8.1 Hz), 7.81(1H, dd, J=2.4 Hz, 8.4 Hz), 8.42 (1H, d, J=2.7 Hz); IR (KBr) 3247, 1634,1530, 1462, 1277, 1198, 1121 cm⁻¹; Anal. Calcd for C₂₈H₂₅ClF₄N₂O₃: C,61.26; H, 4.59; N, 5.10. Found: C, 61.32; H, 4.75; N, 5.07.

Example 330N-[(1RS,2SR)-2-hydroxy-2-(6-phenylpyridin-3-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

N-[(1RS,2SR)-2-(6-Chloropyridin-3-yl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.523 g, 0.953 mmol), phenylboronic acid (0.35 g, 2.86 mmol), tetrakis(triphenylphosphine)palladium(0) (0.22 g, 0.19 mmol) and sodiumcarbonate (0.40 g, 3.81 mmol) were stirred in toluene (10 ml)-water (10ml) at 110° C. for 3 days. The reaction solution was poured into waterand extracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-1/1). Crystallization fromdiisopropyl ether-hexane gave the objective substance.

pale-brown powder yield 0.344 g, 61% mp 174-175° C.; ¹H-NMR (CDCl₃, 300MHz) δ 1.95-2.03 (2H, m), 2.14-2.20 (2H, m), 2.66 (2H, t, J=5.9 Hz),2.82 (1H, dd, J=10.7 Hz, 14.0 Hz), 3.07 (1H, dd, J=4.1 Hz, 14.9 Hz),4.25 (1H, d, J=3.9 Hz), 4.70-4.79 (1H, m), 5.12 (1H, t, J=3.3 Hz), 5.79(1H, d, J=8.4 Hz), 5.89 (1H, tt, J=2.7 Hz, 53.0 Hz), 5.91 (1H, td, J=5.5Hz, 11.4 Hz), 6.21 (1H, d, J=11.7 Hz), 6.98 (1H, dd, J=1.0 Hz, 7.5 Hz),7.03-7.17 (5H, m), 7.32 (1H, t, J=8.0 Hz), 7.40-7.52 (3H, m), 7.75 (1H,d, J=8.1 Hz), 7.90 (1H, dd, J=2.3 Hz, 8.3 Hz), 7.99 (2H, dd, J=2.1 Hz,8.7 Hz), 8.70 (1H, d, J=2.1 Hz); IR (KBr) 3270, 2932, 1640, 1518, 1478,1277, 1200, 1123, 743, 694 cm⁻¹; Anal. Calcd for C₃₄H₃₀F₄N₂O₃: C, 69.14;H, 5.12; N, 4.74. Found: C, 69.04; H, 5.04; N, 4.71.

Example 331N-[(1RS,2SR)-2-(6-chloropyridin-3-yl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-4-fluoronaphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(6-chloropyridin-3-yl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(1.000 g, 2.640 mmol), 4-fluoro-1-naphthoic acid (0.50 g, 2.64 mmol) and1-hydroxybenzotriazole hydrate (0.40 g, 2.64 mmol) in acetonitrile (20ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.51g, 2.64 mmol) was added and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white crystal yield 1.338 g, 92% mp 185-187° C.; ¹H-NMR (CDCl₃-DMSO-d₆,300 MHz). δ 2.91 (1H, dd, J=10.8 Hz, 14.1 Hz), 3.17 (1H, dd, J=3.8 Hz,14.0 Hz), 4.68-4.78 (1H, m), 4.95 (1H, t, J=5.0 Hz), 5.61 (1H, d, J=4.2Hz), 6.00 (1H, tt, J=2.9 Hz, 53.0 Hz), 7.03 (1H, dd, J=7.7 Hz, 10.1 Hz),7.08-7.23 (4H, m), 7.29-7.38 (2H, m), 7.42-7.56 (3H, m), 7.85 (1H, d,J=9.3 Hz, 7.93 (1H, dd, J=2.4 Hz, 8.1 Hz), 8.05 (1H, d, J=8.1 Hz), 8.49(1H, d, J=2.1 Hz); IR (KBr) 3291, 1638, 1624, 1539, 1456, 1196, 1125,837, 766 cm⁻¹; Anal. Calcd for C₂₇H₂₀ClF₅N₂O₃: C, 58.87; H, 3.66; N,5.08. Found: C, 58.84; H, 3.59; N, 5.13.

Example 3324-fluoro-N-[(1RS,2SR)-2-hydroxy-2-(6-phenylpyridin-3-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]naphthalene-1-carboxamide

N-[(1RS,2SR)-2-(6-Chloropyridin-3-yl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-4-fluoronaphthalene-1-carboxamide(0.516 g, 0.937 mmol), phenylboronic acid (0.34 g, 2.81 mmol), tetrakis(triphenylphosphine)palladium(0) (0.22 g, 0.19 mmol) and sodiumcarbonate (0.40 g, 3.74 mmol) were stirred in toluene (10 ml)-water (10ml) at 110° C. for 3 days. The reaction solution was poured into waterand extracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous sodium sulfate and the solvent was evaporated.under reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1-ethyl acetate). Crystallizationfrom diisopropyl ether-hexane gave the objective substance.

brown amorphous powder yield 0.154 g, 28% ¹H-NMR (CDCl₃-DMSO-d₆, 300MHz) δ 2.95 (1H, dd, J=10.8 Hz, 14.4 Hz), 3.10 (1H, dd, J=3.6 Hz, 14.1Hz), 4.82-4.90 (1H, m), 5.12 (1H, t, J=3.9 Hz), 5.32 (1H, d, J=3.9 Hz),5.92 (1H, tt, J=2.8 Hz, 53.1 Hz), 7.02 (1H, dd, J=7.8 Hz, 10.2 Hz), 7.09(1H, d, J=7.8 Hz), 7.15 (1H, s), 7.19-7.53 (9H, m), 7.73 (1H, d, J=9.0Hz), 7.78 (1H, d, J=8.4 Hz), 7.97-8.07 (4H, m), 8.82 (1H, d, J=2.4 Hz);IR (KBr) 3289, 1644, 1601, 1532, 1476, 1264, 1236, 1202, 1123, 758 cm⁻¹;Anal. Calcd for C₃₃H₂₅F₅N₂O₃: C, 66.89; H, 4.25; N, 4.73. Found: C.66.57; H, 4.13; N, 4.82.

Example 3335-chloro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(0.200 g, 0.554 mmol), 5-chloro-1-naphthoate (0.11 g, 0.55 mmol) and1-hydroxybenzotriazole hydrate (85 mg, 0.55 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11g, 0.55 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from ethyl acetate-diisopropyl ether-hexane to give theobjective substance.

white powder yield 0.258 g, 85% mp 174-175° C.; ¹H-NMR (CDCl₃-DMSO-d₆,300 MHz) δ 2.87 (1H, dd, J=10.7 Hz, 14.9 Hz), 2.98 (1H, dd, J=4.7 Hz,14.0 Hz), 4.64 (1H, d, J=3.3 Hz), 4.75-4.84 (1H, m), 5.06 (1H, t, J=4.1Hz), 5.90 (1H, tt, J=2.9 Hz, 53.3 Hz), 6.93 (1H, d, J=9.3 Hz), 7.04-7.16(5H, m), 7.26-7.32 (3H, m), 7.45-7.62 (5H, m), 8.31 (1H, d, J=8.4 Hz);IR (KBr) 3270, 1634, 1537, 1512, 1227, 1192, 1119, 785 cm⁻¹; Anal. Calcdfor C₂₈H₂₁ClF₅NO₃: C, 61.16; H, 3.85; N, 2.55. Found: C, 61.23; H, 3.86;N, 2.39.

Example 3345-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol(0.200 g, 0.554 mmol), 5-fluoro-1-naphthoate (0.11 g, 0.55 mmol) and1-hydroxybenzotriazole hydrate (85 mg, 0.55 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11g, 0.55 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-diisopropyl ether-hexane to give theobjective substance.

white powder yield 0.240 g, 81% mp 178-180° C.; ¹H-NMR (CDCl₃-DMSO-d₆,300 MHz) δ 2.89 (1H, dd, J=10.7 Hz, 14.6 Hz), 2.98 (1H, dd, J=4.5 Hz,14.7 Hz), 4.73 (1H, d, J=3.6 Hz), 4.75-4.84 (1H, m), 5.07 (1H, t, J=3.8Hz), 5.90 (1H, tt, J=2.9 Hz, 53.1 Hz), 6.98 (1H, d, J=9.0 Hz), 7.05-7.17(6H, m), 7.26-7.35 (3H, m), 7.41-7.55 (4H, m), 8.12 (1H, d, J=8.4 Hz);IR (KBr) 3275, 1640, 1541, 1512, 1250, 1229, 1198, 1128, 785 cm⁻¹; Anal.Calcd for C₂₈H₂₁F₆NO₃: C, 63.04; H, 3.97; N, 2.63. Found: C, 63.09; H,4.24; N, 2.56.

Example 335N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(2,3,3-trifluoro-1-propenyl)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1) 2,2,3,3-tetrafluoro-1-(3-methylphenyl)propane-1-one

While stirring a solution of magnesium (14.1 g, 579 mmol) and iodine(one crumb) in diethyl ether (100 ml), 3-methylbromobenzene (90.0 g, 526mmol) in diethyl ether (200 ml) was dropwise added at room temperature.After completion of the dropwise addition, the mixture was stirredovernight at room temperature. The reaction solution was cooled to −78°C. and a solution of 2,2,3,3-tetrafluoropropionic acid (25.61 g, 175.4mmol) in diethyl ether (100 ml) was dropwise added, and the mixture washeated under reflux for 4 hrs. To the reaction solution was dropwiseadded 1N hydrochloric acid under ice-cooling. The diethyl ether layerwas separated, and the aqueous layer was extracted with diethyl ether.The recovered diethyl ether solution was dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theobtained residue was purified by silica gel column chromatography(hexane-hexane/ethyl acetate=15/1) to give the objective substance.

pale-yellow liquid yield 27.97 g, 72% ¹H-NMR (CDCl₃, 300 MHz) δ 2.45(3H, s), 6.29 (1H, tt, J=5.5 Hz, 53.6 Hz), 7.42 (1H, dt, J=1.2 Hz, 7.4Hz), 7.51 (1H, dd, J=0.6 Hz, 7.8 Hz), 7.89-7.92 (2H, m); IR (neat) 1698,1240, 1142, 1115, 1092, 789, 770, 743 cm⁻¹

2) 2,2,3,3-tetrafluoro-1-(3-methylphenyl)propan-1-ol

To a solution of 2,2,3,3-tetrafluoro-1-(3-methylphenyl)propane-1-one(9.11 g, 41.4 mmol) in methanol (50 ml) was added sodium borohydride(0.76 g, 20 mmol) by small portions under ice-cooling and the mixturewas stirred at room temperature for 1 hr. The reaction solution wasdiluted with water, and extracted twice with ethyl acetate. Therecovered organic layer was dried over anhydrous sodium sulfate and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=9/1-3/1) togive the objective substance.

colorless liquid yield 6.131 g, 67% ¹H-NMR (CDCl₃, 200 MHz) δ 2.3.5 (1H,d, J=4.8 Hz), 2.39 (3H, s), 4.95-5.10 (1H, m), 5.97 (1H, ddt, J=3.3 Hz,8.1 Hz, 53.2 Hz), 7.21-7.36 (4H, m); IR (neat) 3426, 1240, 1161, 1107,1059, 762, 743 cm⁻¹

3) O-phenyl O-[2,2,3,3-tetrafluoro-1-(3-methylphenyl)propyl]carbonate

To a solution of 2,2,3,3-tetrafluoro-1-(3-methylphenyl)propan-1-ol(3.814 g, 17.17 mmol) and phenylchlorothionoformate (3.26 g, 18.9 mmol)in acetonitrile (40 ml) was added 4-N,N-dimethylaminopyridine (4.62 g,37.8 mmol) under ice-cooling, and the mixture was stirred overnight atroom temperature. The resulting precipitate was removed by filtrationand washed with acetonitrile. The solvent of the recovered filtrate wasevaporated under reduced pressure and the obtained crude product waspurified by silica gel column chromatography (hexane/ethylacetate=9/1-6/1) to give the objective substance.

colorless liquid yield 6.189 g, 100% ¹H-NMR (CDCl₃, 300 MHz) δ 2.41 (3H,s), 5.89 (1H, tt, J=5.0 Hz, 53.0 Hz), 6.56 (1H, dd, J=10.7 Hz, 14.0 Hz),7.08 (2H, d, J=7.5 Hz), 7.21-7.49 (7H, m); IR (neat) 1591, 1489, 1279,1211, 1127, 1107, 1065, 774, 689 cm⁻¹

4) 1-methyl-3-(2,2,3,3-tetrafluoropropyl)benzene

A solution of O-phenylO-[2,2,3,3-tetrafluoro-1-(3-(methylphenyl)propy]thiocarbonate (6.189 g,17.27 mmol), tributyltin hydride (7.49 g, 25.7 mmol) and2,2′-azobis(isobutyronitrile) (0.56 g, 3.43 mmol) in benzene (50 ml) wasstirred at 80° C. for 6 hrs. After cooling the reaction solution to roomtemperature, the solvent was evaporated under recduced pressure and theobtained residue was purified by silica gel column chromatography(hexane) to give the objective substance.

colorless liquid yield 1.412 g, 40% ¹H-NMR (CDCl₃, 300 MHz) δ 2.36 (3H,s), 3.24 (2H, t, J=17.7 Hz), 5.69 (1H, tt, J=3.5 Hz, 53.7 Hz), 7.08-7.15(3H, m), 7.23 (1H, d, J=7.8 Hz); IR (neat) 1165, 1101, 1057 cm⁻¹

5) ethyl3-(4-fluorophenyl)-2-[3-(2,2,3,3-tetrafluoropropyl)benzyl]-3-oxopropionate

A solution of 1-methyl-3-(2,2,3,3-tetrafluoropropyl)benzene (1.363 g,6.611 mmol), N-bromosuccinimide (1.18 g, 6.61 mmol) and2,2′-azobis(isobutyronitrile) (30 mg) in carbon tetrachloride (20 ml)was heated under reflux for 1.5 hrs. After cooling the reaction solutionto room temperature, the white precipitate was collected by filtrationand the precipitate was washed with hexane. The solvent of the recoveredfiltrate was evaporated under reduced pressure to give a crude productof 3-(2,2,3,3-tetrafluoropropyl)benzyl bromide as a colorless liquid.

To a solution of ethyl (4-fluorobenzoyl)acetate (1.39 g, 6.61 mmol) in1,2-dimethoxyethane (30 ml) was added a suspension (0.26 g, 6.61 mmol)of 60% sodium hydride in liquid paraffin under ice-cooling, and themixture was stirred as it was for 0.5 hr. A solution of3-(2,2,3,3-tetrafluoropropyl)benzyl bromide obtained above in1,2-dimethoxyethane (10 ml) was added thereto at room temperature, andthe mixture was stirred overnight at room temperature. The reactionsolution was poured into water, and extracted twice with ethyl acetate.The recovered organic layer was dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the obtainedresidue was purified by silica gel column chromatography (hexane/ethylacetate=15/1−9/1) to give the objective substance.

yellow liquid yield 1.849 g, 68% ¹H-NMR (CDCl₃, 300 MHz) δ 1.12 (3H, t,J=7.1 Hz), 3.22 (2H, t, J=18.0 Hz), 3.32 (1H, d, J=7.5 Hz), 3.33 (1H, d,J=7.2 Hz), 4.10 (2H, dq, J=1.7 Hz, 7.2 Hz), 4.56 (1H, t, J=7.7 Hz), 5.63(1H, tt, J=3.3 Hz, 53.6 Hz), 7.08-7.24 (6H, m), 7.97 (2H, dd, 5.6 Hz,8.9 Hz); IR (neat) 1738, 1688, 1599, 1508, 1233, 1159, 1101, 849 cm⁻¹

6) ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(2,2,3,3-tetrafluoropropyl)benzyl]propionate

While stirring zinc chloride (1.22 g, 8.92 mmol) in diethyl ether (30ml), sodium borohydride (0.68 g, 17.8 mmol) was added at roomtemperature, and the mixture was stirred as it was for 2 hrs. Insolublematerial in the mixture was removed by filtration and washed withdiethyl ether to give a solution of zinc borohydride in diethyl ether. Asolution of ethyl3-(4-fluorophenyl)-2-[3-(2,2,3,3-tetrafluoropropyl)benzyl]-3-oxopropionate(1.849 g, 4.462 mmol) in diethyl ether (20 ml) was added to the obtainedsolution under ice-cooling, and the mixture was stirred as it was for 20min. To the reaction solution was added dilute hydrochloric acid bysmall portions to decompose excess zinc borohydride, and the mixture wasextracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous magnesium sulfate and the solvent was evaporatedunder reduced pressure. The obtained crude product was purified bysilica gel column chromatography (hexane/ethyl acetate=3/1) to give theobjective substance.

colorless liquid yield 1.378 g, 74% ¹H-NMR (CDCl₃, 300 MHz) δ 0.91 (3H,t, J=7.1 Hz), 2.92 (1H, d, J=2.7 Hz), 2.98 (2H, s), 3.20 (2H, t, J=17.9Hz), 3.87 (2H, dq, J=2.0 Hz, 7.2 Hz), 5.01 (1H, t, J=3.6 Hz), 5.66 (1H,tt, J=3.3 Hz, 53.7 Hz), 7.01-7.11 (5H, m), 7.22 (1H, t, J=7.5 Hz), 7.37(2H, dd, J=5.3 Hz, 8.6 Hz); IR (neat) 3445, 1715, 1607, 1512, 1375,1346, 1223, 1159, 1100, 1057, 839 cm⁻¹

7)(4RS,5SR)-5-(4-fluorophenyl)-4-[3-(2,2,3,3-tetrafluoropropyl)benzyl]-1,3-oxazolidin-2-one

A mixture of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(2,2,3,3-tetrafluoropropyl)benzyl]propionate(1.378 g, 3.309 mmol), sodium hydroxide (0.26 g, 6.62 mmol), methanol(10 ml), water (5 ml) and tetrahydrofuran (10 ml) was stirred overnightat room, temperature. The reaction solution was concentrated and dilutedwith water, acidified with 1N hydrochloric acid and extracted twice withethyl acetate. The recovered organic layer was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure togive a crude product of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(2,2,3,3-tetrafluoropropyl)benzyl]propionicacid as a liquid.

To a solution of the liquid obtained above in tetrahydrofuran (30 ml)were added triethylamine (0.55 ml, 3.97 mmol) and diphenylphosphorylazide (1.00 g, 3.64 mmol), and the mixture was stirred at 65° C.overnight. The solvent of the reaction solution was evaporated underreduced pressure and the obtained crude product was purified by silicagel column chromatography (hexane/ethyl acetate=3/1−1/1).Crystallization from diisopropyl ether-hexane gave the objectivesubstance.

white crystal yield 1.022 g, 80% mp 91-93° C.; ¹H-NMR (CDCl₃, 300 MHz) δ2.24 (1H, dd, J=10.1 Hz, 14.0 Hz), 2.31 (1H, dd, J=4.8 Hz, 13.5 Hz),3.22 (2H, t, J=17.9 Hz), 4.21-4.28 (1H, m), 5.15 (1H, s), 5.72 (1H, tt,J=3.0 Hz, 53.9 Hz), 5.79 (1H, d, J=7.8 Hz), 6.95 (1H, s), 6.99 (1H, d,J=7.8 Hz), 7.10-7.18 (3H, m), 7.28 (1H, t, J=7.7 Hz), 7.36 (2H, dd,J=5.1 Hz, 8.4 Hz); IR (KBr) 3241, 1757, 1740, 1512, 1343, 1223, 1167,1094, 1051, 835, 712 cm⁻¹; Anal. Calcd for C₁₉H₁₆F₅NO₂: C, 59.22; H,4.19; N, 3.63. Found: C, 59.20; H, 4.22; N, 3.66.

8)(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(2,3,3-trifluoro-1-propenyl)phenyl]propan-1-ol

(4RS,5SR)-5-(4-fluorophenyl)-4-[3-(2,2,3,3-tetrafluoropropyl)benzyl]-1,3-oxazolidin-2-one(0.880 g, 2.284 mmol) and sodium hydroxide (0.37 g, 9.14 mmol) wereheated under reflux in ethanol (10 ml)-water (0.5 ml) for 3 hrs. Thereaction solution was diluted with water and extracted twice with ethylacetate. The recovered organic layer was dried over anhydrous sodiumsulfate and passed through APS-silica gel. The solvent was evaporatedunder reduced pressure and the residue was crystallized from ethylacetate-diethyl ether-hexane to give the objective substance.

white crystal yield 0.462 g, 60% mp 98-99° C.; ¹H-NMR (CDCl₃, 300 MHz) δ2.36 (1H, dd, J=10.2 Hz, 13.5 Hz), 2.81 (1H, dd, J=3.3 Hz, 13.8 Hz),3.26-3.32 (1H, m), 4.67 (1H, d, J=4.8 Hz), 6.07 (1H, d, J=37.2 Hz), 6.15(1H, dt, J=7.2 Hz, 53.8 Hz), 7.05-7.14 (3H, m), 7.28-7.43 (5H, m); IR(KBr) 3100-2750, 1508, 1406, 1362, 1223, 1103, 1042 cm⁻¹; Anal. Calcdfor C₁₈H₁₇F₄NO: C, 63.71; H, 5.05; N, 4.13. Found: C, 63.49; H, 5.07; N,4.12.

9)N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(2,3,3-trifluoro-1-propenyl)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(2,3,3-trifluoro-1-propenyl)phenyl]propan-1-ol(0.100 g, 0.295 mmol), 6,7-dihydro-5H-benzo[a]cyclohepten-1-carboxylicacid (55 mg, 0.29 mmol) and 1-hydroxybenzotriazole hydrate (45 mg, 0.29mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (56 mg, 0.29mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white powder yield 0.122 g, 81% mp 165-167° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.95-2.03 (2H, m), 2.16-2.22 (2H, m), 2.66 (2H, t, J=6.2 Hz), 2.76(1H, dd, J=10.8 Hz, 14.7 Hz), 3.00 (1H, dd, J=4.4 Hz, 14.6 Hz), 3.69(1H, d, J=4.2 Hz), 4.64-4.73 (1H, m), 5.04 (1H, t, J=3.9 Hz), 5.72 (1H,d, J=8.1 Hz), 5.89 (1H, td, J=5.6 Hz, 11.3 Hz), 6.06 (1H, d, J=37.2 Hz),6.14 (1H, dt, J=7.2 Hz, 53.7 Hz), 6.17 (1H, d, J=11.7 Hz), 6.97 (1H, dd,J=1.5 Hz, 7.8 Hz), 7.03-7.19 (5H, m), 7.29-7.34 (2H, m), 7.41-7.48 (3H,m); IR (KBr) 3272, 2938, 1638, 1512, 1345, 1227, 1182, 1101, 1038, 772cm⁻¹; Anal. Calcd for C₃₀H₂₇F₄NO₂: C, 70.72; H, 5.34; N, 2.75. Found: C,70.43; H, 5.26; N, 2.71.

Example 3364-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(2,3,3-trifluoro-1-propenyl)benzyl]ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(2,3,3-trifluoro-1-propenyl)phenyl]propan-1-ol(0.100 g, 0.295 mmol), 4-fluoro-1-naphthoic acid (56 mg, 0.29 mmol) and1-hydroxybenzotriazole hydrate (45 mg, 0.29 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (56 mg,0.29 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance.

white powder yield 0.122 g, 81% mp 184-185° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 2.81 (1H, dd, J=10.7 Hz, 14.3 Hz), 3.06 (1H, dd, J=4.1 Hz, 14.6 Hz),3.49 (1H, d, J=3.3 Hz), 4.73-4.82 (1H, m), 5.10 (1H, t, J=3.8 Hz), 5.89(1H, d, J=8.1 Hz), 6.05 (1H, d, J=37.2 Hz), 6.12 (1H, dt, J=7.2 Hz, 53.7Hz), 7.01 (1H, dd, J=7.7 Hz, 10.1 Hz), 7.09 (2H, t, J=8.6 Hz), 7.16-7.57(9H, m), 7.75 (1H, d, J=8.7 Hz), 8.08 (1H, d, J=8.4 Hz); IR (KBr) 3275,1642, 1512, 1229, 1051, 837, 760 cm⁻¹; Anal. Calcd for C₂₉H₂₂F₅NO₂: C,68.10; H, 4.34; N, 2.74. Found: C, 67.77; H, 4.19; N, 2.74.

Example 337 tert-butylN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(2,2,3,3-tetrafluoropropyl)benzyl]ethyl]carbamate

1) tert-butyl(4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-[3-(2,2,3,3-tetrafluoropropyl)benzyl]-1,3-oxazolidine-3-carboxylate

A solution of(4RS,5SR)-5-(4-fluorophenyl)-4-[3-(2,2,3,3-tetrafluoropropyl)benzyl]-1,3-oxazolidin-2-one(2.368 g, 6.145 mmol), di-tert-butyl dicarbonate (1.61 g, 7.37 mmol) and4-N,N-dimethylaminopyridine (75 mg, 0.61 mmol) in acetonitrile (30 ml)was stirred overnight at room temperature. The solvent of the reactionsolution was evaporated under reduced pressure and the obtained residuewas purified by silica gel column chromatography (hexane/ethylacetate=3/1−1/1) to give the objective substance.

pale-yellow liquid yield 3.014 g, 100% ¹H-NMR (CDCl₃, 200 MHz) δ 1.51(9H, s), 2.57 (1H, dd, J=9.0 Hz, 14.0 Hz), 2.90 (1H, dd, J=4.4 Hz, 14.4Hz), 3.11 (2H, br t, J=18.3 Hz), 4.77-4.87 (1H, m), 5.67 (1H, d, J=8.0Hz), 5.69 (1H, tt, J=3.2 Hz, 53.8 Hz), 6.60-6.64 (2H, m), 6.93 (2H, t,J=8.6 Hz), 7.03-7.16 (4H, m); IR (neat) 2982, 1817, 1723, 1514, 1360,1302, 1227, 1155, 1101, 1067 cm⁻¹

2) tert-butylN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(2,2,3,3-tetrafluoropropyl)benzyl]ethyl]carbamate

To a solution of tert-butyl(4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-[3-(2,2,3,3-tetrafluoropropyl)benzyl]-1,3-oxazolidine-3-carboxylate(3.014 g, 6.209 mmol) in tetrahydrofuran (30 ml) was added a solution ofsodium hydroxide (0.26 g, 6.52 mmol) in methanol (10 ml) underice-cooling, and the mixture was stirred at 0° C. for 0.5 hr. Thereaction solution was diluted with ethyl acetate, washed with water,dried over anhydrous magnesium sulfate and passed through silica gel.The solvent was evaporated under reduced pressure. The obtained residuewas crystallized from ethyl acetate-diisopropyl ether-hexane to give theobjective substance.

white crystal yield 2.367 g, 83% mp 168-169° C.; ¹H-NMR (CDCl₃-DMSO-d₆,300 MHz) δ 1.30 (9H, s), 2.64-2.78 (2H, m), 3.21 (2H, t, J=17.7 Hz),4.05 (1H, br s), 4.54 (1H, s), 4.87 (1H, br s), 5.08 (1H, br d, J=8.4Hz), 5.70 (1H, tt, J=3.9 Hz, 53.4 Hz), 7.01-7.10 (5H, m), 7.21 (1H, t,J=7.7 Hz), 7.41 (2H, dd, J=5.6 Hz, 8.6 Hz); IR (KBr) 3349, 1680, 1535,1227, 1173, 1113, 1007, 837 cm⁻¹; Anal. Calcd for C₂₃H₂₆F₅NO₃: C, 60.13;H, 5.70; N, 3.05. Found: C, 60.04; H, 5.73; N, 2.91.

Example 338N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(2,2,3,3-tetrafluoropropyl)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1)(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(2,2,3,3-tetrafluoropropyl)phenyl]propan-1-ol

A mixture of tert-butylN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(2,2,3,3-tetrafluoropropyl)benzyl]ethyl]carbamate(2.188 g, 4.762 mmol) and trifluoroacetic acid (10 ml) were stirred atroom temperature for 1 hr. The reaction solution was evaporated underreduced pressure, diluted with water, alkalified with potassiumcarbonate, and extracted twice with ethyl acetate. The recovered organiclayer was dried over anhydrous sodium sulfate and passed throughAPS-silica gel. The solvent was evaporated under reduced pressure togive the objective substance.

yellow liquid yield 1.720 g, 100% ¹H-NMR (CDCl₃, 300 MHz) δ 2.35 (1H,dd, J=10.4 Hz, 13.7 Hz) 2.80 (1H, dd, J=3.3 Hz, 13.5 Hz), 3.24 (2H, t,J=18.6 Hz), 3.25-3.29 (1H, m), 4.66 (1H, d, J=4.8 Hz), 5.70 (1H, tt,J=3.2 Hz, 53.8 Hz), 7.04-7.16 (5H, m), 7.28 (1H, t, J=7.7 Hz), 7.37 (2H,dd, J=5.4 Hz, 8.7 Hz); IR (neat) 3365-2860, 1605, 1508, 1223, 1157,1101, 1057, 837 cm⁻¹

2)N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(2,2,3,3-tetrafluoropropyl)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(2,2,3,3-tetrafluoropropyl)phenyl]propan-1-ol(0.300 g, 0.835 mmol), 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylicacid (0.16 g, 0.83 mmol) and 1-hydroxybenzotriazole hydrate (0.13 g,0.83 mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.16 g,0.83 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-diisopropyl ether-hexane to give theobjective substance.

white powder yield 0.325 g, 74% mp 165-166° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.95-2.04 (2H, m), 2.16-2.22 (2H, m), 2.64-2.68 (2H, m), 2.74 (1H, dd,J=10.5 Hz, 14.4 Hz), 2.99 (1H, dd; J=4.1 Hz, 14.6 Hz), 3.22 (2H, t,J=18.0 Hz), 3.75 (1H, d, J=3.9 Hz), 4.65-4.74 (1H, m), 5.02 (1H, t,J=3.9 Hz), 5.68 (1H, tt, J=3.4 Hz, 53.7 Hz), 5.70 (1H, d, J=9.0 Hz),5.91 (1H, td, J=5.5 Hz, 11.7 Hz), 6.21 (1H, d, J=11.7 Hz), 6.91 (1H, d,J=7.8 Hz), 7.02-7.10 (4H, m), 7.14-7.17 (3H, m), 7.7.28 (1H, t, J=7.2Hz), 7.43 (2H, dd, J=5.3 Hz, 8.6 Hz); IR (KBr) 3281, 1638, 1514, 1229,1105, 835 cm⁻¹; Anal. Calcd for C₃₀H₂₈F₅NO₂: C, 68.04; H, 5.33; N, 2.65.Found: C, 67.89; H, 5.34; N, 2.47.

Example 3394-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(2,2,3,3-tetrafluoropropyl)benzyl]ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(2,2,3,3-tetrafluoropropyl)phenyl]propan-1-ol(0.300 g, 0.835 mmol), 4-fluoro-1-naphthoic acid (0.16 g, 0.83 mmol) and1-hydroxybenzotriazole hydrate (0.13 g, 0.83 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.16g, 0.83 mol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from ethyl acetate-diisopropyl ether-hexane to give theobjective substance.

white powder yield 0.349 g, 79% mp 172-173° C.; ¹H-NMR (CDCl₃-DMSO-d₆,300 MHz) δ 2.86 (1H, dd, J=10.7 Hz, 14.3 Hz), 2.97 (1H, dd, J=4.2 Hz,14.1 Hz), 3.20 (2H, t, J=17.9 Hz), 4.73-4.82 (1H, m), 4.92 (1H, d, J=3.6Hz), 5.06 (1H, t, J=3.5 Hz), 5.69 (1H, tt, J=3.5 Hz, 53.5 Hz), 6.90 (1H,d, J=9.0 Hz), 7.01 (1H, dd, J=7.7 Hz, 10.1 Hz), 7.08 (2H, t, J=8.4 Hz),7.14-7.29 (5H, m), 7.43 (1H, t, J=7.5 Hz), 7.50-7.55 (3H, m), 7.73 (1H,d, J=8.4 Hz), 8.06 (1H, d, J=8.1 Hz); IR (KBr) 3274, 1644, 1539, 1514,1236, 1103, 1055, 837, 760 cm⁻¹; Anal. Calcd for C₂₉H₂₃F₆NO₂: C, 65.54;H, 4.36; N, 2.64. Found: C, 65.53; H, 4.39; N, 2.34.

Example 3405-chloro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(2,2,3,3-tetrafluoropropyl)benzyl]ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(2,2,3,3-tetrafluoropropyl)phenyl]propan-1-ol(0.300 g, 0.835 mmol), 5-chloro-1-naphthoic acid (0.16 g, 0.83 mmol) and1-hydroxybenzotriazole hydrate (0.13 g, 0.83 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.16g, 0.83 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1−1/1). Crystallization fromethyl acetate-diisopropyl ether-hexane gave the objective substance.

white crystal yield 0.285 g, 62% mp 174-175° C.; ¹H-NMR (CDCl₃-DMSO-d₆,300 MHz) δ 2.85 (1H, dd, J=11.0 Hz, 14.3 Hz), 2.98 (1H, dd, J=3.6 Hz,14.7 Hz), 3.21 (2H, t, J=18.0 Hz), 4.75-4.85 (1H, m), 4.90 (1H, d, J=3.6Hz), 5.05 (1H, t, J=3.5 Hz), 5.69 (1H, tt, J=3.6 Hz, 53.7 Hz), 7.00 (1H,d, J=9.0 Hz), 7.05-7.29 (8H, m), 7.45-7.56 (5H, m), 8.30 (1H, d, J=8.4Hz); IR (KBr) 3275, 1638, 1539, 1514, 1233, 1100, 837, 785, 708 cm⁻¹;Anal. Calcd for C₂₉H₂₃ClF₅NO₂: C, 63.57; H, 4.23; N, 2.56. Found: C,63.59; H, 4.14; N, 2.68.

Example 341 tert-butylN-[(1RS,2SR)-1-[3-(1,2-difluoro-2-methylpropyl)benzyl]-2-(4-fluorophenyl)-2-hydroxyethyl]carbamate

1) ethyl 2-methyl-2-(3-methylphenyl)propionate

To a solution of ethyl 3-tolylacetate (30.92 g, 173.5 mmol) inN,N-dimethylformamide (150 ml) was added a suspension (15.3 g, 382 mmol)of 60% sodium hydride in liquid paraffin under ice-cooling, and themixture was stirred at room temperature for 0.5 hr. Methyl iodide (32.2ml, 520 mmol) was added thereto at 0° C., and the mixture was stirredovernight at room temperature. The reaction solution was poured intowater and extracted twice with ethyl acetate. The recovered organiclayer was dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the obtained residue was purifiedby silica gel column chromatography (hexane/ethyl acetate=50/1−15/1) togive the objective substance.

colorless liquid yield 30.22 g, 84% ¹H-NMR (CDCl₃, 200 MHz) δ 1.19 (3H,t, J=7.1 Hz), 1.56 (6H, s), 2.35 (3H, s), 4.12 (2H, q, J=7.2 Hz),7.03-7.22 (4H, m); IR (neat) 2976, 1730, 1252, 1146, 702 cm⁻¹

2) 2-methyl-2-(3-methylphenyl)propan-1-ol

To a suspension of lithium aluminum hydride (3.52 g, 92.9 mmol) intetrahydrofuran (150 ml) was dropwise added a solution of ethyl2-methyl-2-(3-methylphenyl)propionate (19.16 g, 92.88 mmol) intetrahydrofuran (100 ml) under ice-cooling, and the mixture was stirredat room temperature for 1 hr. After ice-cooling the reaction solution,water (3.5 ml), 15% aqueous sodium hydroxide solution (3.5 ml) and water(9 ml) were successively added dropwise to decompose excess lithiumaluminum hydride. The mixture was stirred as it was at room temperaturefor 2 hrs. The resulting precipitate was removed by filtration, and theprecipitate was washed with ethyl acetate. The solvent of the recoveredfiltrate was evaporated under reduced pressure and the obtained residuewas purified by silica gel column chromatography (hexane/ethylacetate=6/1) to give the objective substance.

colorless liquid yield 12.99 g, 85% ¹H-NMR (CDCl₃, 300 MHz) δ 1.22 (1H,t, J=6.6 Hz), 1.33 (6H, s), 2.36 (3H, s), 3.61 (2H, d, J=6.9 Hz), 7.04(1H, d, J=7.2 Hz), 7.17-7.27 (3H, m); IR (neat) 3370, 2963, 1042, 783,704 cm⁻¹

3) 2-methyl-2-(3-methylphenyl)propanal

To a solution of oxalyl chloride (15.1 g, 119 mmol) in tetrahydrofuran(150 ml) was dropwise added a solution of dimethyl-sulfoxide (16.8 ml,237 mmol) in tetrahydrofuran (50 ml) at −78° C., and the mixture wasstirred for 5 min. A solution of 2-methyl-2-(3-methylphenyl)propan-1-ol(12.99 g, 79.09 mmol) in tetrahydrofuran (80 ml) was added at −78° C.,and the mixture was stirred for 15 min. Triethylamine (66.1 ml, 475mmol) was added thereto, and the mixture was warmed to room temperature.The reaction mixture was poured into water and extracted twice withethyl acetate. The recovered organic layer was dried over anhydrousmagnesium sulfate and the solvent was evaporated under reduced pressure.The obtained crude product was purified by silica gel columnchromatography (hexane/ethyl acetate=15/1) to give the objectivesubstance.

pale-yellow liquid yield 11.72 g, 91% ¹H-NMR (CDCl₃, 300 MHz) δ 1.45(6H, s), 2.36 (3H, s), 7.07-7.7.12 (3H, m), 7.27 (1H, t, J=8.0 Hz), 9.49(1H, s); IR (neat) 2975, 1728, 785, 704 cm⁻¹

4) 1-(1,2-difluoro-2-methylpropyl)-3-methylbenzene

To a solution of (diethylamino)sulfur trifluoride (7.31 g, 45.4 mmol) inmethylene chloride (20 ml) at −78° C. was added a solution of2-methyl-2-(3-methylphenyl)propanal (7.360 g, 45.37 mmol) in methylenechloride (10 ml) at room temperature, and the mixture was stirred atroom temperature for 0.5 hr. To the reaction solution was added water,and the mixture was stirred. The methylene chloride layer was separatedand the aqueous layer was extracted with diethyl ether. The recoveredorganic layer was dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the obtained residue waspurified by silica gel column chromatography (hexane-hexane/ethylacetate=30/1) to give the objective substance.

colorless liquid yield 2.747 g, 33% ¹H-NMR (CDCl₃, 300 MHz) δ 1.33 (3H,dd, J=1.5 Hz, 16.2 Hz), 1.40 (3H, dd, J=2.0 Hz, 16.4 Hz), 2.37 (3H, s),5.29 (1H, dd, J=13.8 Hz, 45.3 Hz), 7.14-7.18 (3H, m), 7.27 (1H, t, J=7.8Hz); IR (neat) 2988, 1387, 1157, 1036, 775, 702 cm⁻¹

5) ethyl2-[3-(1,2-difluoro-2-methylpropyl)benzyl]-3-(4-fluorophenyl)-3-oxopropionate

A solution of 1-(1,2-difluoro-2-methylpropyl)-3-methylbenzene (2.747 g,14.91 mmol), N-bromosuccinimide (2.65 g, 14.9 mmol) and2,2′-azobis(isobutyronitrile) (0.1 g) in carbon tetrachloride (30 ml)was heated under reflux for 1.5 hrs. After cooling the reaction solutionto room temperature, white precipitate was collected by filtration andwashed with hexane. The solvent of the recovered filtrate was evaporatedunder reduced pressure to give a crude product of3-(1,2-difluoro-2-methylpropyl)benzyl bromide as a yellow liquid.

To a solution of ethyl (4-fluorobenzoyl)acetate (3.13 g, 14.9 mmol) in1,2-dimethoxyethane (40 ml) was added a suspension (0.60 g, 14.9 mmol)of 60% sodium hydride in liquid paraffin under ice-cooling, and themixture was stirred as it was for 0.5 hr. A solution of the liquidobtained above in 1,2-dimethoxyethane (10 ml) was added thereto at roomtemperature, and the mixture was stirred overnight at room temperature.The reaction solution was poured into water, and extracted twice withethyl acetate. The recovered organic layer was dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe obtained residue was purified by silica gel column chromatography(hexane/ethyl acetate=15/1−9/1) to give the objective substance.

yellow liquid yield 3.484 g, 60% ¹H-NMR (CDCl₃, 300 MHz) δ 1.12 (3H, t,J=7.1 Hz), 1.23-1.39 (6H, m), 3.34 (1H, d, J=7.5 Hz), 3.35 (1H, d, J=7.2Hz), 4.10 (2H, q, J=7.1 Hz), 4.55 (0.5H, t, J=7.7 Hz), 4.58 (0.5H, t,J=7.5 Hz), 5.25 (0.5H, dd, J=14.1 Hz, 45.0 Hz), 5.26 (0.5H, dd, J=13.4Hz, 45.2 Hz), 7.10 (2H, t, J=8.4 Hz), 7.16-7.24 (4H, m), 7.97 (2H, dd,J=5.4 Hz, 9.0 Hz); IR (neat) 2986, 1736, 1686, 1599, 1508, 1269, 1236,1159, 1032, 849 cm⁻¹

6) ethyl(2RS,3RS)-2-[3-(1,2-difluoro-2-methylpropyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionate

While stirring zinc chloride (2.37 g, 17.4 mmol) in diethyl ether (50ml), sodium borohydride (1.32 g, 34.8 mmol) was added at roomtemperature, and the mixture was stirred as it was for 2 hrs. Theinsoluble material in the mixture was removed by filtration and washedwith diethyl ether to give a solution of zinc borohydride in diethylether. A solution of ethyl2-[3-(1,2-difluoro-2-methylpropyl)benzyl]-3-(4-fluorophenyl)-3-oxopropionate(3.412g, 8.695 mmol) in diethyl ether (20 ml) was added to the obtainedsolution under ice-cooling, and the mixture was stirred as it was for 20min. To the reaction solution was added dilute hydrochloric acid bysmall portions to decompose excess zinc borohydride, and the mixture wasextracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous magnesium sulfate and the solvent was evaporatedunder reduced pressure. The obtained crude product was purified bysilica gel column chromatography (hexane/ethyl acetate=3/1) to give theobjective substance.

colorless liquid yield 2.919 g, 85% ¹H-NMR (CDCl₃, 200 MHz) δ 0.92 (3H,t, J=7.1 Hz), 1.25-1.42 (6H, m), 2.89-2.93 (1H, m), 2.96-3.05 (3H, m),3.86 (2H, q, J=7.1 Hz), 5.00 (1H, t, J=3.7 Hz), 5.24 (1H, dd, J=14.2 Hz,45.2 Hz), 7.00-7.29 (6H, m), 7.37 (2H, dd, J=5.2 Hz, 8.8 Hz); IR (neat)3445, 2986, 1728, 1605, 1510, 1375, 1225, 1159, 1032, 839 cm⁻¹

7)(4RS,5SR)-4-[3-(1,2-difluoro-2-methylpropyl)benzyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one

A mixture of ethyl(2RS,3RS)-2-[3-(1,2-difluoro-2-methylpropyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionate(2.849 g, 7.223 mmol), sodium hydroxide (0.58 g, 14.4 mmol), methanol(10 ml), water (10 ml) and tetrahydrofuran (10 ml) was stirred overnightat room temperature. The reaction solution was concentrated, dilutedwith water, acidified with hydrochloric acid, and extracted twice withethyl acetate. The recovered organic layer was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure togive a crude product of(2RS,3RS)-2-[3-(1,2-difluoro-2-ethylpropyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionicacid as a liquid.

To a solution of the liquid obtained above in tetrahydrofuran (40 ml)were added triethylamine (1.21 ml, 8.67 mmol) and diphenylphosphorylazide (2.19 g, 7.95 mmol), and the mixture was stirred at 65° C.overnight. The solvent of the reaction solution was evaporated underreduced pressure and the obtained crude product was purified by silicagel column chromatography (hexane/ethyl acetate=3/1−1/1) to give theobjective substance.

white solid yield 2.245 g, 86% mp 130-131° C.; ¹H-NMR (CDCl₃, 300 MHz) δ1.28-1.41 (6H, m), 2.20-2.36 (2H, m), 4.21-4.30 (1H, m), 4.97 (1H, s),5.24 (0.5H, dd, J=13.7 Hz, 44.9 Hz), 5.25 (0.5H, dd, J=14.0 Hz, 45.2Hz), 5.80 (1H, d, J=8.1 Hz), 7.01-7.39 (8H, m); IR (KBr) 3250, 1742,1514, 1236, 1223, 1022, 849 cm⁻¹; Anal. Calcd for C₂₀H₂₀F₃NO₂.0.1H₂O: C,65.78; H, 5.58; N, 3.84. Found: C, 65.64; H, 5.50; N, 3.96.

8) tert-butyl(4RS,5SR)-4-[3-(1,2-difluoro-2-methylpropyl)benzyl]-5-(4-fluorophenyl)-2-oxo-1,3-oxazolidine-3-carboxylate

A solution of(4RS,5SR)-4-[3-(1,2-difluoro-2-methylpropyl)benzyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one(2.124 g, 5.845 mmol), di-tert-butyl dicarbonate (1.53 g, 7.01 mmol) and4-N,N-dimethylaminopyridine (71 mg, 0.58 mmol) in acetonitrile (40 ml)was stirred overnight at room temperature. The solvent of the reactionsolution was evaporated under reduced pressure and the obtained residuewas purified by silica gel column chromatography (hexane/ethylacetate=3/1−2/1) to give the objective substance.

pale-yellow liquid yield 2.633 g, 97% ¹H-NMR (CDCl₃, 300 MHz) δ1.24-1.38 (6H, m), 1.49 (4.5H, s), 1.53 (4.5H, s), 2.55-2.64 (1H, m),2.85-2.96 (1H, m), 4.79-4.86 (1H, m), 5.10 (0.5H, dd, J=13.2 Hz, 45.0Hz), 5.17 (0.5H, dd, J=14.6 Hz, 45.2 Hz), 5.66 (0.5H, d, J=7.2 Hz), 5.67(0.5H, d, J=6.6 Hz), 6.59-6.65 (1H, m), 6.67 (0.5H, s), 6.82 (0.5H, s),6.91-6.98 (2H, m), 7.04-7.17 (4H, m); IR (neat) 2984, 1817, 1723, 1514,1358, 1308, 1229, 1155, 1069 cm⁻¹

9) tert-butylN-[(1RS,2SR)-1-[3-(1,2-difluoro-2-methylpropyl)benzyl]-2-(4-fluorophenyl)-2-hydroxyethyl]carbamate

To a solution of tert-butyl(4RS,5SR)-4-[3-(1,2-difluoro-2-methylpropyl)benzyl]-5-(4-fluorophenyl)-2-oxo-1,3-oxazolidine-3-carboxylate(2.584 g, 5.575 mmol) in tetrahydrofuran (20 ml) was added a solution ofsodium hydroxide (0.22 g, 5.57 mmol) in methanol (5 ml) underice-cooling, and the mixture was stirred at room temperature for 1 hr.The reaction solution was diluted with ethyl acetate, washed with water,dried over anhydrous magnesium sulfate and passed through silica gel.The solvent was evaporated under reduced pressure to give the objectivesubstance.

white solid yield 2.300 g, 94% mp 148-149° C.; ¹H-NMR (CDCl₃, 300 MHz) δ1.28-1.41 (6H, m), 1.34 (9H, s), 2.65 (1H, dd, J=10.1 Hz, 14.3 Hz), 2.80(1H, dd, J=4.7 Hz, 14.3 Hz), 3.38 (1H, br s), 4.09 (1H, br s), 4.50 (1H,br d, J=6.9 Hz), 4.90 (1H, br s), 5.27 (1H, dd, J=13.7 Hz, 45.2 Hz),7.07 (2H, t, J=8.7 Hz), 7.11-7.13 (2H, m), 7.18-7.31 (2H, m), 7.37 (2H,dd, J=5.6 Hz, 8.6 Hz); IR (KBr) 3366, 2988, 1682, 1532, 1514, 1225,1171, 1007 cm⁻¹; Anal. Calcd for C₂₄H₃₀F₃NO₃: C, 65.89; H, 6.91; N,3.20. Found: C, 65.62; H, 6.88; N, 3.22.

Example 342N-[(1RS,2SR)-1-[3-(1,2-difluoro-2-methylpropyl)benzyl]-2-(4-fluorophenyl)-2-hydroxyethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1)(1RS,2SR)-2-amino-3-[3-(1,2-difluoro-2-methylpropyl)phenyl]-1-(4-fluorophenyl)propan-1-ol

A mixture of tert-butylN-[(1RS,2SR)-1-[3-(1,2-difluoro-2-methylpropyl)benzyl]-2-(4-fluorophenyl)-2-hydroxyethyl]carbamate(2.139 g, 4.889 mmol) and trifluoroacetic acid (10 ml) was stirred atroom temperature for 1 hr. The reaction solution was evaporated underreduced pressure, diluted with water, alkalified with potassiumcarbonate, and extracted twice with ethyl acetate. The recovered organiclayer was dried over anhydrous sodium sulfate and passed throughAPS-silica gel. The solvent was evaporated under reduced pressure togive the objective substance.

pale-yellow liquid yield 1.650 g, 100% ¹H-NMR (CDCl₃, 300 MHz) δ 1.31(3H, d, J=15.3 Hz), 1.38 (3H, d, J=14.7 Hz), 2.36 (1H, dd, J=10.2 Hz,13.5 Hz), 2.81 (1H, dd, J=3.2 Hz, 13.4 Hz), 3.25-3.32 (1H, m), 4.66 (1H,d, J=4.8 Hz), 5.28 (1H, dd, J=13.8 Hz, 45.3 Hz), 7.08 (2H, t, J=8.7 Hz),7.11-7.33 (4H, m), 7.37 (2H, dd, J=5.6 Hz, 8.6 Hz); IR (neat) 3360-2860,1605, 1508, 1387, 1373, 1223, 1157, 1034, 839 cm⁻¹

2)N-[(1RS,2SR)-1-[3-(1,2-difluoro-2-methylpropyl)benzyl]-2-(4-fluorophenyl)-2-hydroxyethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2SR)-2-amino-3-[3-(1,2-difluoro-2-methylpropyl)phenyl]-1-(4-fluorophenyl)propan-1-ol(0.200 g, 0.593 mmol), 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylicacid (0.11 g, 0.59 mmol) and 1-hydroxybenzotriazole hydrate (91 mg, 0.59mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g,0.59 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1−1/1). Crystallization fromdiisopropyl ether-hexane gave the objective substance.

white powder yield 0.184 g, 61% mp 102-104° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.25-1.39 (6H, m), 1.95-2.03 (2H, m), 2.16-2.22 (2H, m), 2.66 (2H, t,J=5.7 Hz), 2.69-2.82 (1H, m), 2.98-3.03 (1H, m), 3.79 (0.5H, d, J=3.9Hz), 3.82 (0.5H, d, J=3.9 Hz), 4.65-4.74 (1H, m), 5.02 (1H, t, J=3.6Hz), 5.24 (0.5H, dd, J=14.0 Hz, 45.2 Hz), 5.27 (0.5H, dd, J=13.5 Hz,45.0 Hz), 5.70 (1H, d, J=8.7 Hz), 5.88-5.96 (1H, m), 6.20 (1H, d, J=12.3Hz), 6.91-6.95 (1H, m), 7.02-7.34 (8H, m), 7.43 (2H, dd, J=5.3 Hz, 8.6Hz); IR (KBr) 3295, 2938, 1638, 1510, 1225, 1034, 772 cm⁻¹; Anal. Calcdfor C₃₁H₃₂F₃NO₂.0.1H₂O: C, 73.09; H, 6.37; N, 2.75. Found: C, 72.87; H,6.31; N, 2.62.

Example 3434-fluoro-N-[(1RS,2SR)-1-[3-(1,2-difluoro-2-methylpropyl)benzyl]-2-(4-fluorophenyl)-2-hydroxyethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-3-[3-(1,2-difluoro-2-methylpropyl)phenyl]-1-(4-fluorophenyl)propan-1-ol(0.200 g, 0.593 mmol), 4-fluoro-1-naphthoic acid (0.11 g, 0.59 mmol) and1-hydroxybenzotriazole hydrate (91 mg, 0.59 mmol) in acetonitrile (10ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11g, 0.59 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate=3/1−1/1). Crystallization fromdiisopropyl ether-hexane gave the objective substance.

white powder yield 0.218 g, 72% mp 163-165° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.24-1.38 (6H, m), 2.74-2.87 (1H, m), 3.07 (1H, dd, J=4.1 Hz, 14.3Hz), 3.62-3.64 (1H, m), 4.74-4.83 (1H, m), 5.07 (0.5H, t, J=4.1 Hz),5.08 (0.5H, t, J=3.9 Hz), 5.22 (0.5H, dd, J=14.9 Hz, 45.2 Hz), 5.27(0.5H, dd, J=13.4 Hz, 44.9 Hz), 5.86 (0.5H, d, J=8.1 Hz), 5.88 (0.5H, d,J=8.1 Hz), 6.96-7.37 (8H, m), 7.43-7.57 (4H, m), 7.77-7.84 (1H, m), 8.08(1H, d, J=8.1 Hz); IR (KBr) 3291, 1642, 1626, 1512, 1231, 837, 768 cm⁻¹;Anal. Calcd for 3C₃₀H₂₇F₄NO₂.0.2H₂O: C, 70.22; H, 5.38; N, 2.73. Found:C, 69.96; H, 5.24; N, 2.70.

Example 344N-[(1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-(4-neopentylbenzyl)ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

1) 4-neopentylbenzoic acid

While stirring a suspension of aluminum chloride (4.43 g, 33.2 mmol) inmethylene chloride (20 ml), a solution of trichloroacetyl chloride (6.04g, 33.2 mmol) in methylene chloride (10 ml) was added dropwise at −78°C. The reaction solution was stirred for 15 min warmed to −50° C., and asolution of neopentylbenzene (4.922 g, 33.20 mmol) in methylene chloride(10 ml) was added. The mixture was stirred overnight at roomtemperature. The reaction solution was poured into ice water and themethylene chloride layer of the mixture was separated. The aqueous layerwas extracted with diethyl ether. The recovered organic layer was driedover anhydrous magnesium sulfate and the solvent was evaporated underreduced pressure and the obtained residue was dissolved intetrahydrofuran (30 ml), a solution of potassium hydroxide (3.73 g, 66.4mmol) in water (40 ml) was added, and the mixture was stirred at roomtemperature for 10 min. The reaction solution was diluted with diethylether and water and the aqueous layer was separated. The obtainedaqueous solution was acidified with conc. hydrochloric acid, andextracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure to give the objective substance.

brown crystal yield 5.343 g, 84%

Recrystallization from diisopropyl ether-hexane gave white crystals.

mp 193-194° C.; ¹H-NMR (CDCl₃, 300 MHz) δ 0.92 (9H, s), 2.58 (2H, s),2.24 (2H, d, J=8.1 Hz), 8.02 (2H, d, J=8.4 Hz), 8.02 (1H, br s); IR(KBr) 3100-2550, 1682, 1426, 1319, 1296, 951, 731 cm⁻¹; Anal. Calcd forC₁₂H₁₆O₂: C, 74.97; H, 8.39. Found: C, 74.85; H, 8.47.

2) 4-neopentylbenzyl alcohol

To a suspension of lithium aluminum hydride (1.13 g, 29.9 mmol) intetrahydrofuran (50 ml) was added dropwise a solution of4-neopentylbenzoic acid (3.830 g, 19.92 mmol) in tetrahydrofuran (30 ml)under ice-cooling, and the mixture was stirred overnight at roomtemperature. After ice-cooling the reaction solution, water (1 ml), a15% aqueous sodium hydroxide solution (1 ml) and water (2.5 ml) weresuccessively added dropwise to decompose excess lithium aluminumhydride. The mixture was stirred as it was at room temperature for 2hrs. The resulting precipitate was removed by filtration, and theprecipitate was washed with ethyl acetate. The solvent of the recoveredfiltrate was evaporated under reduced pressure and the obtained residuewas purified by silica gel column chromatography (hexane/ethylacetate=6/1−3/1) to give the objective substance.

yellow liquid yield 2.446 g, 69% ¹H-NMR (CDCl₃, 300 MHz) δ 0.90 (9H, s),1.62 (1H, t, J=5.9 Hz), 2.49 (2H, s), 4.67 (2H, d, J=5.7 Hz), 7.12 (2H,d, J=8.1 Hz), 7.27 (2H, d, J=7.8 Hz); IR (neat) 3330, 2951, 1364, 1017cm⁻¹

3) ethyl 3-(3-chlorophenyl)-2-(4-neopentylbenzyl)-3-oxopropionate

To a solution of 4-neopentylbenzyl alcohol (2.446 g, 13.72 mmol) andtriethylamine (2.87 ml, 20.6 mmol) in ethyl acetate (50 ml) was addeddropwise a solution of methanesulfonyl chloride (1.89 g, 16.5 mmol) inethyl acetate (10 ml) under ice-cooling, and the mixture was stirred asit was for 10 min. The resulting precipitate was removed by filtration,and the precipitate was washed with diethyl ether. The solvent of therecovered filtrate was evaporated under reduced pressure to give a crudeproduct of methanesulfonic acid ester as a yellow liquid.

To a solution of ethyl (3-chlorobenzoyl)acetate (3.11 g, 13.7 mmol) in1,2-dimethoxyethane (20 ml) was added a suspension (0.55 g, 13.7 mmol)of 60% sodium hydride in liquid paraffin under ice-cooling, and themixture was stirred as it was for 0.5 hr. A solution of methanesulfonicacid ester obtained above in 1,2-dimethoxyethane (20 ml) was addedthereto at room temperature, and the mixture was stirred at roomtemperature for 3 days. The reaction solution was poured into water, andextracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the obtained residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=15/1) to give the objectivesubstance.

pale-yellow liquid yield 4.648 g, 88% ¹H-NMR (CDCl₃, 300 MHz) δ 0.85(9H, s), 1.13 (3H, t, J=7.1 Hz), 2.42 (2H, s), 3.28-3.31 (2H, m),4.07-4.15 (2H, m), 4.55 (1H, t, J=7.4 Hz), 7.00 (2H, d, J=7.8 Hz), 7.09(2H, d, J=8.1 Hz), 7.36 (1H, t, J=7.7 Hz), 7.51 (1H, ddd, J=1.1 Hz, 1.9Hz, 8.0 Hz), 7.78 (1H, ddd, J=1.1 Hz, 1.7 Hz, 7.7 Hz), 7.89 (1H, t,J=1.8 Hz); IR (neat) 2953, 1738, 1694, 1229 cm⁻¹

4) ethyl(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-(4-neopentylbenzyl)propionate

While stirring zinc chloride (3.22 g, 23.6 mmol) in diethyl ether (30ml), sodium borohydride (1.78 g, 47.2 mmol) was added at roomtemperature, and the mixture was stirred as it was for 2 hrs. Insolublematerial in the mixture was removed by filtration and washed withdiethyl ether to give a solution of zinc borohydride in diethyl ether.To the obtained solution was added a solution of ethyl3-(3-chlorophenyl)-2-(4-neopentylbenzyl)-3-oxopropionate (4.564 g, 11.80mmol) in diethyl ether (30 ml) under ice-cooling, and the mixture wasstirred as it was for 20 min. To the reaction solution was added dilutehydrochloric acid by small portions to decompose excess zincborohydride, and the mixture was extracted twice with ethyl acetate. Therecovered organic layer was dried over anhydrous magnesium sulfate andthe solvent was evaporated under reduced pressure. The obtained crudeproduct was purified by silica gel column chromatography (hexane/ethylacetate=15/1−6/1) to give the objective substance.

colorless liquid yield 3.828 g, 83% ¹H-NMR (CDCl₃, 200 MHz) δ 0.86 (9H,s), 0.95 (3H, t, J=7.2 Hz), 2.42 (2H, s), 2.84-3.00 (3H, m), 3.13 (1H,d, J=2.6 Hz), 3.91 (2H, q, J=7.1 Hz), 5.03 (1H, t, J=3.1 Hz), 6.98 (4H,s), 7.26 (3H, s), 7.42 (1H, s); IR (neat) 3468, 2951, 1726, 1709, 1476,1375, 1364, 1236, 1184, 1032 cm⁻¹

5)(4RS,5SR)-5-(3-chlorophenyl)-4-(4-neopentylbenzyl)-1,3-oxazolidin-2-one

A mixture of ethyl(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-(4-neopentylbenzyl)propionate(3.756 g, 9.657 mmol), sodium hydroxide (0.77 g, 19.3 mmol), methanol(20 ml), water (10 ml) and tetrahydrofuran (20 ml) was stirred overnightat room temperature. The reaction solution was concentrated, dilutedwith water, acidified with hydrochloric acid, and extracted twice withethyl acetate. The recovered organic layer was dried over anhydroussodium sulfate and the solvent was evaporated under reduced pressure togive a crude product of(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-(4-neopentylbenzyl)propionicacid as a white solid.

To a solution of the solid obtained above in tetrahydrofuran (30 ml)were added triethylamine (1.62 ml, 11.6 mmol) and diphenylphosphorylazide (2.92,g, 10.6 mmol) and the mixture was stirred at 65° C.overnight. The solvent of the reaction solution was evaporated underreduced pressure and the obtained crude product was purified by silicagel column chromatography (hexane/ethyl acetate=3/1−1/1).Crystallization from ethyl acetate-diisopropyl ether-hexane gave theobjective substance.

white crystal yield 2.517 g, 73% mp 197-198° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 0.87 (9H, s), 2.18 (1H, dd, J=11.0 Hz, 13.6 Hz), 2.30 (1H, dd, J=4.0Hz, 13.8 Hz), 2.44 (2H, s), 4.18-4.30 (1H, m), 4.99 (1H, br s), 5.76(1H, d, J=8.2 Hz), 6.92 (2H, d, J=8.0 Hz), 7.04 (2H, d, J=8.0 Hz),7.24-7.38 (4H, m); IR (KBr) 3268, 2959, 1740, 1240, 1017, 791 cm⁻¹;Anal. Calcd for C₂₁H₂₄ClNO₂: C, 70.48; H, 6.76; N, 3.91. Found: C,70.56; H, 7.00; N, 3.62.

6) (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-(4-neopentylphenyl)propan-1-ol

(4RS,5SR)-5-(3-Chlorophenyl)-4-(4-neopentylbenzyl)-1,3-oxazolidin-2-one(2.335 g, 6.525 mmol) and sodium hydroxide (1.04 g, 26.1 mmol) washeated under reflux in ethanol (30 ml)-water (1 ml) for 5 hrs. Thereaction solution was diluted with water, and the mixture was stirred asit was for 0.5 hr. The resulting precipitate was collected and washedwith water and diisopropyl ether-hexane to give the objective substance.

white powder yield 1.814 g, 84% mp 118-120° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 0.88 (9H, s), 2.31 (1H, dd, J=10.5 Hz, 13.8 Hz), 2.45 (2H, s), 2.72(1H, dd, J=3.3 Hz, 13.8 Hz), 3.29 (1H, ddd, J=3.3 Hz, 4.8 Hz, 10.5 Hz),4.67 (1H, d, J=4.5 Hz), 7.00-7.06 (5H, m), 7.24-7.32 (2H, m), 7.42 (1H,s); IR (KBr) 3130-2770, 2953, 1576, 1476, 1420, 1364, 1192, 1040, 949,855, 779, 729 cm⁻¹; Anal. Calcd for C₂₀H₂₆ClNO: C, 72.38; H, 7.90; N,4.22. Found: C, 72.24; H, 7.97; N, 4.02.

7)N-[(1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-(4-neopentylbenzyl)ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-(4-neopentylphenyl)propan-1-ol(0.300 g, 0.904 mmol), 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylicacid (0.17 g, 0.90 mmol) and 1-hydroxybenzotriazole hydrate (0.14 g,0.90 mmol) in acetonitrile (10 ml)-N,N-dimethylformamide (2 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 g,0.90 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-diisopropyl ether-hexane to give theobjective substance.

white powder yield 0.377 g, 83% mp 147-149° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 0.88 (9H, s), 1.95-2.04 (2H, m), 2.17-2.23 (2H, m), 2.46 (2H, s),2.62-2.71 (3H, m), 2.97 (1H, dd, J=4.2 Hz, 14.4 Hz), 4.38 (1H, d, J=4.2Hz), 4.63-4.72 (1H, m), 5.04 (1H, t, J=3.8 Hz), 5.69 (1H, d, J=7.5 Hz),5.99 (1H, td, J=5.4 Hz, 12.0 Hz), 6.33 (1H, d, J=11.7 Hz), 6.88 (1H, dd,J=1.2 Hz, 7.5 Hz), 7.01 (1H, t, J=7.5 Hz), 7.05 (4H, s), 7.14 (1H, d,J=6.3 Hz), 7.27-7.35 (3H, m), 7.48 (1H, s); IR (KBr) 3376, 3331, 2959,1626, 1528, 779, 766 cm⁻¹; Anal. Calcd for C₃₂H₃₆ClNO₂: C, 76.55; H,7.23; N, 2.79. Found: C, 76.38; H, 7.19; N, 2.52.

Example 3454-fluoro-N-[(1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-(4-neopentylbenzyl)ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-7(3-chlorophenyl)-3-(4-neopentylphenyl)propan-1-ol(0.300 g, 0.904 mmol), 4-fluoro-1-naphthoic acid (0.17 g, 0.90 mmol) and1-hydroxybenzotriazole hydrate (0.14 g, 0.90 mmol) in acetonitrile (10ml)-N,N-dimethylformamide (2 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 g,0.90 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-diisopropyl ether-hexane to give theobjective substance.

white powder yield 0.300 g, 66% mp 150-151° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 0.89 (9H, s), 2.48 (2H, s), 2.73 (1H, dd, J=11.3 Hz, 14.6 Hz), 3.04(1H, dd, J=4.2 Hz, 14.4 Hz), 4.19 (1H, d, J=4.5 Hz), 4.72-4.81 (1H, m),5.11 (1H, t, J=3.9 Hz), 5.86 (1H, d, J=8.1 Hz), 6.94 (1H, dd, J=8.1 Hz,9.9 Hz), 7.04-7.12 (5H, m), 7.27-7.40 (3H, m), 7.46-7.58 (3H, m), 7.94(1H, d, J=8.1 Hz), 8.08 (1H, d, J=7.5 Hz); IR (KBr) 3275, 2955, 1642,1626, 1541, 1426, 1264, 1236, 1051, 760 cm⁻¹; Anal. Calcd forC₃₁H₃₁ClFNO₂: C, 73.87; H, 6.20; N, 2.78. Found: C, 73.69; H, 6.02; N,2.59.

Example 3465-chloro-N-[(1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-(4-neopentylbenzyl)ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-(4-neopentylphenyl)propan-1-ol(0.300 g, 0.904 mmol), 5-chloro-1-naphthoic acid (0.19 g, 0.90 mmol) and1-hydroxybenzotriazole hydrate (0.14 g, 0.90 mmol) in acetonitrile (10ml)-N,N-dimethylformamide (2 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 g,0.90 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-diisopropyl ether-hexane to give theobjective substance.

white crystal yield 0.367 g, 78% mp 168-169° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 0.88 (9H, s), 2.46 (2H, s), 2.81 (1H, dd, J=10.6 Hz, 14.6Hz), 2.94 (1H, dd, J=4.6 Hz, 14.4 Hz), 4.72-4.86 (1H, m), 5.04-5.11 (2H,m), 6.97-7.14 (5H, m), 7.23-7.37 (4H, m), 7.42-7.58 (4H, m), 7.67 (1H,d, J=8.4 Hz), 8.29 (1H, d, J=8.6 Hz); IR (KBr) 3272, 2957, 1636, 1537,785 cm⁻¹; Anal. Calcd for C₃₁H₃₁Cl₂NO₂: C, 71.54; H, 6.00; N, 2.69.Found: C, 71.63; H, 6.09; N, 2.58.

Example 347 tert-butylN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxyethyl-1-[3-(2,2,3,3-tetrafluoropropionyl)benzyl]]carbamate

1) ethyl3-(4-fluorophenyl)-2-[3-(2,2,3,3-tetrafluoropropionyl)benzyl]-3-oxopropionate

A solution of 2,2,3,3-tetrafluoro-1-(3-methylphenyl)propan-1-one (7.484g, 33.99 mmol), N-bromosuccinimide (6.05 g, 34.0 mmol) and2,2′-azobis(isobutyronitrile) (0.2 g) in carbon tetrachloride (40 ml)was heated under reflux for 1.5 hrs. After cooling the reaction solutionto room temperature, the white precipitate was removed by filtration,and washed with hexane. The solvent of the recovered filtrate wasevaporated under reduced pressure to give a pale-yellow liquid.

To a solution of ethyl (4-fluorobenzoyl)acetate (7.15 g, 34.0 mmol) in1,2-dimethoxyethane (50 ml) was added a suspension (1.36 g, 34.0 mmol)of 60% sodium hydride in liquid paraffin under ice-cooling, and themixture was stirred as it was for 0.5 hr. A solution of the liquidobtained above in 1,2-dimethoxyethane (30 ml) was added thereto at roomtemperature, and the mixture was stirred overnight at room temperature.The reaction solution was poured into water, and extracted twice withethyl acetate. The recovered organic layer was dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe obtained residue was purified by silica gel column chromatography(hexane/ethyl acetate=15/1−9/1) to give the objective substance.

yellow, liquid yield 6.608 g, 45% ¹H-NMR (CDCl₃, 300 MHz) δ 1.12 (3H, t,J=7.2 Hz), 3.41 (2H, d, J=7.5 Hz), 3.40-4.15 (2H, m), 4.59 (1H, t, J=7.4Hz), 6.28 (1H, tt, J=5.6 Hz, 52.5 Hz), 7.13 (2H, t, J=8.7 Hz), 7.44 (1H,t, J=8.0 Hz), 7.59 (1H, d, J=7.5 Hz), 7.93-7.96 (2H, m), 8.01 (2H, dd,J=5.6 Hz, 8.9 Hz); IR (neat) 1736, 1686, 1599, 1508, 1302, 1273, 1238,1159, 1115, 849 cm⁻¹

2) ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(2,2,3,3-tetrafluoro-1-hydroxypropyl)benzyl]propionate

While stirring zinc chloride (4.16 g, 30.5 mmol) in diethyl ether (50ml), sodium borohydride (2.31 g, 61.1 mmol) was added at roomtemperature, and the mixture was stirred as it was for 2 hrs. Insolublematerial in the mixture was removed by filtration and washed withdiethyl ether to give a solution of zinc borohydride in diethyl ether.To the obtained solution was added a solution of ethyl3-(4-fluorophenyl)-2-[3-(2,2,3,3-tetrafluoropropionyl)benzyl]-3-oxopropionate(6.540 g, 15.27 mmol) in diethyl ether (30 ml) under ice-cooling, andthe mixture was stirred as it was for 20 min. To the reaction solutionwas added dilute hydrochloric acid by small portions to decompose excesszinc borohydride, and the mixture was extracted twice with ethylacetate. The recovered organic layer was dried over anhydrous magnesiumsulfate and the solvent was evaporated under reduced pressure. Theobtained crude product was purified by silica gel column chromatography(hexane/ethyl acetate=3/1−1/1) to give the objective substance.

pale-yellow liquid yield 5.958 g, 90% ¹H-NMR (CDCl₃, 300 MHz) δ0.90 (3H,t, J=7.1 Hz), 2.78 (1H, s), 2.93-3.03 (4H, m), 3.78-3.89 (2H, m),4.93-5.03 (2H, m), 5.96 (1H, ddt, J=2.4 Hz, 8.5 Hz, 53.2 Hz), 7.03 (2H,t, J=8.7 Hz), 7.11-7.15 (1H, m), 7.19 (1H, d, J=7.2 Hz), 7.24-7.28 (2H,m), 7.34 (2H, dd, J=5.4 Hz, 9.0 Hz); IR (neat) 3418, 1715, 1607, 1512,1377, 1229, 1186, 1159, 1100, 1057, 839 cm⁻¹

3)(4RS,5SR)-5-(4-fluorophenyl)-4-[3-(2,2,3,3-tetrafluoro-1-hydroxypropyl)benzyl]-1,3-oxazolidin-2-one

A mixture of ethyl(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(2,2,3,3-tetrafluoro-1-hydroxypropyl)benzyl]propionate(5.878 g, 13.59 mmol), sodium hydroxide (1.09 g, 27.2 mmol), methanol(20 ml), water (30 ml) and tetrahydrofuran (20 ml) was stirred overnightat room temperature. The reaction solution was concentrated, dilutedwith water, acidified with hydrochloric acid, and extracted twice withethyl acetate. The recovered organic layer was dried over anhydroussodium sulfate and the solvent was evaporated under reduced pressure togive a crude product of(2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[3-(2,2,3,3-tetrafluoro-1-hydroxypropyl)benzyl]propionicacid as a liquid.

To a solution of the liquid obtained above in tetrahydrofuran (50 ml)were added triethylamine (2.27 ml, 16.3 mmol) and diphenylphosphorylazide (4.12 g, 15.0 mmol) were added, and the mixture was stirred at 65°C. overnight. The solvent of the reaction solution was evaporated underreduced pressure and the obtained crude product was purified by silicagel column chromatography (hexane/ethyl acetate=3/1−1/2) to give theobjective substance.

pale-yellow liquid yield 5.001 g, 92% ¹H-NMR (CDCl₃, 300 MHz) δ2.14-2.38 (2H, m), 4.17-4.25 (1H, m), 4.34-4.42 (0.5H, m), 4.87-4.89(0.5H, m), 4.96 (0.5H, br s), 5.02 (0.5H, br s), 5.73 (0.5H, d, J=8.7Hz), 5.78 (0.5H, d, J=8.7 Hz), 6.08 (1H, dt, J=9.7 Hz, 53.4 Hz), 6.85(0.5H, s), 6.99-7.36 (7.5H, m); IR (neat) 3304, 1744, 1514, 1236, 1101,1067, 735 cm⁻¹

4)(4RS,5SR)-5-(4-fluorophenyl)-4-[3-(2,2,3,3-tetrafluoropropionyl)benzyl]-1,3-oxazolidin-2-one

While stirring(4RS,5SR)-5-(4-fluorophenyl)-4-[3-(2,2,3,3-tetrafluoro-1-hydroxypropyl)benzyl]-1,3-oxazolidin-2-one(5.779 g, 14.40 mmol) and triethylamine (16.1 ml, 115 mmol) in dimethylsulfoxide (20 ml), a solution of sulfur trioxide pyridine complex (9.17g, 57.6 mmol) in dimethyl sulfoxide (30 ml) was added at roomtemperature, and the mixture was stirred as it was overnight. Thereaction mixture was poured into water, acidified with conc.hydrochloric acid, and extracted twice with ethyl acetate. The recoveredorganic layer was dried over anhydrous magnesium sulfate and the solventwas evaporated under reduced pressure. The obtained crude product waspurified by silica gel column chromatography (hexane/ethylacetate=2/1−1/1) to give the objective substance.

yellow solid yield 3.772 g, 66%

Recrystallization from diisopropyl ether gave a white powder.

mp 149-150° C.; ¹H-NMR (CDCl₃, 300 MHz) δ 2.41 (2H, d, J=7.5 Hz), 4.31(1H, q, J=7.4 Hz), 5.69 (1H, s), 5.79 (1H, d, J=8.1 Hz), 6.27 (1H, tt,J=5.4 Hz, 52.6 Hz), 7.11 (2H, t, J=8.6 Hz), 7.31-7.36 (3H, m), 7.46 (1H,t, J=7.7 Hz), 7.68 (1H, s), 7.96 (1H, d, J=8.1 Hz); IR (KBr) 3250, 1740,1690, 1516, 1240, 1115, 1096 cm⁻¹; Anal. Calcd for C₁₉H₁₄F₅NO₃: C,57.15; H, 3.53; N, 3.51. Found: C, 57.12; H; 3.57; N, 3.41.

5) tert-butyl(4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-[3-(2,2,3,3-tetrafluoropropionyl)benzyl]-1,3-oxazolidine-3-carboxylate

A solution of(4RS,5SR)-5-(4-fluorophenyl)-4-[3-(2,2,3,3-tetrafluoropropionyl)benzyl]-1,3-oxazolidin-2-one(2.199 g, 5.507 mmol), di-tert-butyl dicarbonate (1.44 g, 6.61 mmol) and4-N,N-dimethylaminopyridine (67 mg, 0.55 mmol) in acetonitrile (30 ml)was stirred overnight at room temperature. The solvent of the reactionsolution was evaporated under reduced pressure and the obtained residuewas purified by silica gel column chromatography (hexane/ethylacetate=3/1). Crystallization from diisopropyl ether-hexane gave theobjective substance.

white crystal yield 2.178 g, 79% mp 116-118° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.52 (9H, s), 2.69 (1H, dd, J=9.0 Hz, 14.4 Hz), 2.99 (1H, dd, J=4.1Hz, 14.3 Hz), 4.83 (1H, ddd, J=4.4 Hz, 7.1 Hz, 9.2 Hz), 5.68 (1H, d,J=7.2 Hz), 6.27 (1H, tt, J=5.6 Hz, 52.5 Hz), 6.94 (2H, t, J=8.7 Hz),7.04 (1H, d, J=7.8 Hz), 7.13 (2H, dd, J=5.1 Hz, 8.4 Hz), 7.28 (1H, t,J=8.0 Hz), 7.33 (1H, s), 7.84 (1H, d, J=8.1 Hz); IR (KBr) 1806, 1701,1516, 1372, 1159, 1113, 1076 cm⁻¹; Anal. Calcd for C₂₄H₂₂F₅NO₅: C,57.72; H, 4.44; N, 2.80. Found: C, 57.66; H, 4.41; N, 2.66.

6) tert-butylN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxyethyl-1-[3-(2,2,3,3-tetrafluoropropionyl)benzyl]]carbamate

To a solution of tert-butyl,(4RS,5SR)-5-(4-fluorophenyl)-2-oxo-4-[3-(2,2,3,3-tetrafluoropropionyl)benzyl]-1,3-oxazolidine-3-carboxylate(2.030 g, 4.065 mmol) in tetrahydrofuran (20 ml) was added a solution ofsodium hydroxide (0.16 g, 4.06 mmol) in methanol (10 ml) underice-cooling, and the mixture was stirred at room temperature for 1 hr.The reaction solution was diluted with ethyl acetate, washed with water,dried over anhydrous magnesium sulfate and passed through silica gel.The solvent was evaporated under reduced pressure and the obtainedresidue was crystallized from ethyl acetate-diisopropyl ether-hexane togive the objective substance.

white powder yield 1.692 g, 88% mp 157-158° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.31 (9H, s), 2.76 (1H, dd, J=9.9 Hz, 14.4 Hz), 2.86 (1H, dd, J=4.2Hz, 14.1 Hz), 3.07 (1H, s), 4.04-4.13 (1H, m), 4.65 (1H, br d, J=9.3Hz), 4.94 (1H, s), 6.29 (1H, tt, J=5.6 Hz, 52.5 Hz), 7.08 (2H, t, J=8.7Hz), 7.34-7.48 (4H, m), 7.81 (1H, s), 7.93 (1H, d, J=6.9 Hz); IR (KBr)3353, 1682, 1534, 1514, 1242, 1225, 1171, 1113, 1005 cm⁻¹; Anal. Calcdfor C₂₃H₂₄F₅NO₄: C, 58.35; H, 5.11; N, 2.96. Found: C, 58.12; H, 4.94;N, 2.79.

Example 3484-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(2,2,3,3-tetrafluoropropionyl)benzyl]ethyl]naphthalene-1-carboxamide

A solution of tert-butylN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxyethyl-1-[3-(2,2,3,3-tetrafluoropropionyl)benzyl]]carbamate(0.423 g, 0.893 mmol) in trifluoroacetic acid (5 ml) was stirred at roomtemperature for 15 min. The reaction solution was evaporated underreduced pressure, diluted with water, alkalified with potassiumcarbonate, and extracted twice with ethyl acetate. The recovered organiclayer was dried over anhydrous sodium sulfate and the solvent wasevaporated under reduced pressure to give a pale-yellow liquid.

While stirring the liquid obtained above, 4-fluoro-1-naphthoic acid(0.17 g, 0.89 mmol) and 1-hydroxybenzotriazole hydrate (0.14 g, 0.89mmol) in acetonitrile (15 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 g,0.89 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate=2/1−1/1). Crystallization fromdiisopropyl ether-hexane gave the objective substance.

white crystal yield 0.364 g, 75% mp 160-162° C.; ¹H-NMR (CDCl₃-DMSO-d₆,300 MHz) δ 2.94 (1H, dd, J=10.5 Hz, 14.4 Hz), 3.01 (1H, dd, J=5.1 Hz,14.1 Hz), 4.66 (1H, d, J=3.6 Hz), 4.74-4.83 (1H, m), 5.07 (1H, t, J=3.6Hz), 6.26 (1H, tt, J=5.6 Hz, 52.5 Hz), 6.97-7.11 (4H, m), 7.24 (1H, dd,J=5.3 Hz, 8.0 Hz), 7.38-7.61 (6H, m), 7.68 (1H, d, J=8.7 Hz), 7.90 (1H,s), 7.96 (1H, d, J=8.1 Hz), 8.06 (1H, d, J=8.1 Hz); IR (KBr) 3277, 1703,1644, 1626, 1601, 1512, 1231, 1113, 835, 762 cm⁻¹; Anal. Calcd forC₂₉H₂₁F₆NO₃: C, 63.86; H, 3.88; N, 2.57. Found: C, 63.49; H, 3.49; N,2.45.

Example 3494-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-[1-(1,1,2,2-tetrafluoroethyl)vinyl]benzyl]ethyl]naphthalene-1-carboxamide

To a solution of methyltriphenylphosphonium bromide (0.36 g, 1.00 mmol)in tetrahydrofuran (15 ml) was added tert-potassium tert-butoxide (0.11g, 1.00 mmol) at room temperature, and the mixture was stirred for 0.5hr. A solution of4-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(2,2,3,3-tetrafluoropropionyl)benzyl]ethyl]naphthalene-1-carboxamide(0.181 g, 0.332 mmol) in tetrahydrofuran (10 ml) was added thereto, andthe mixture was stirred at room temperature for 3 days. The reactionsolution was poured into water, and extracted twice with ethyl acetate.The recovered organic layer was dried over anhydrous magnesium sulfateand the solvent was evaporated under reduced pressure. The obtainedcrude product was purified by silica gel column chromatography(hexane/ethyl acetate=2/1−1/1). Crystallization from diisopropylether-hexane gave the objective substance.

white solid yield 0.146 g, 81% mp 162-163° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 2.86 (1H, dd, J=10.6 Hz, 14.2 Hz), 2.99 (1H, dd, J=6.6 Hz,14.2 Hz), 4.73-4.86 (1H, m), 5.01-5.06 (2H, m), 5.63 (1H, s), 5.75 (1H,tt, J=4.6 Hz, 53.2 Hz), 5.87 (1H, t, J=1.7 Hz), 6.96-7.27 (9H, m),7.37-7.57 (4H, m), 7.67 (1H, d, J=8.6 Hz), 8.06 (1H, d, J=8.4 Hz); IR(KBr) 3262, 1642, 1626, 1601, 1537, 1510, 1264, 1229, 1111, 1053, 833,758 cm⁻¹; Anal. Calcd for C₃₀H₂₃F₆NO₂.0.3H₂O: C, 65.64; H, 4.33; N,2.55. Found: C, 65.53; H, 4.04; N, 2.37.

Example 3505-chloro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(2,2,3,3-tetrafluoropropionyl)benzyl]ethyl]naphthalene-1-carboxamide

A solution of tert-butylN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxyethyl-1-[3-(2,2,3,3-tetrafluoropropionyl)benzyl]]carbamate(0.462 g, 0.976 mmol) in trifluoroacetic acid (5 ml) was stirred at roomtemperature for 15 min. The reaction solution was evaporated underreduced pressure, diluted with water, alkalified with potassiumcarbonate, and extracted twice with ethyl acetate. The recovered organiclayer was dried over anhydrous sodium sulfate and the solvent wasevaporated under reduced pressure to give a pale-yellow liquid.

While stirring the liquid obtained above, 5-chloro-1-naphthoate (0.20 g,0.98 mmol) and 1-hydroxybenzotriazole hydrate (0.15 g, 0.98 mmol) inacetonitrile (15 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.19 g, 0.98 mmol) was added, and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solutionand dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure and the obtained residue was purified by silicagel column chromatography (hexane/ethyl acetate=2/1−1/1).Crystallization from diisopropyl ether-hexane gave the objectivesubstance.

white crystal yield 0.429 g, 78% mp 154-155° C.; ¹H-NMR (CDCl₃-DMSO-d₆,300 MHz) δ 2.94 (1H, dd, J=10.7 Hz, 14.0 Hz), 3.04 (1H, dd, J=4.1 Hz,14.0 Hz), 4.75-4.85 (1H, m), 4.87 (1H, d, J=3.6 Hz), 5.05 (1H, t, J=3.9Hz), 6.28 (1H, tt, J=5.5 Hz, 52.4 Hz), 7.09 (2H, t, J=8.6 Hz), 7.23 (1H,t, J=8.0 Hz), 7.33 (1H, t, J=9.0 Hz), 7.44-7.56 (6H, m), 7.61 (1H, d,J=7.5 Hz), 7.91 (1H, s), 7.98 (1H, t, J=8.4 Hz), 8.30 (1H, d, J=8.1 Hz);IR (KBr) 3279, 1703, 1640, 1537, 1512, 1231, 1113, 787 cm⁻¹; Anal. Calcdfor C₂₉H₂₁ClF₅NO₃.0.5H₂O: C, 61.01; H, 3.88; N, 2.45. Found: C, 61.21;H, 3.96; N, 2.82.

Example 3515-chloro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-[1-(1,1,2,2-tetrafluoroethyl)vinyl]benzyl]ethyl]naphthalene-1-carboxamide

To a solution of methyltriphenylphosphonium bromide (0.39 g, 1.10 mmol)in tetrahydrofuran (15 ml) was added potassium tert-butoxide (0.12 g,1.10 mmol) at room temperature, and the mixture was stirred for 0.5 hr.A solution of5-chloro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(2,2,3,3-tetrafluoropropionyl)benzyl]ethyl]naphthalene-1-carboxamide(0.206 g, 0.367 mmol) in tetrahydrofuran (10 ml) was added, and themixture was stirred at room temperature for 3 days. The reactionsolution was poured into water, and extracted twice with ethyl acetate.The recovered organic layer was dried over anhydrous magnesium sulfateand the solvent was evaporated under reduced pressure. The obtainedcrude product was purified by silica gel column chromatography(hexane/ethyl acetate=2/1−1/1). Crystallization from diisopropylether-hexane gave the objective substance.

white powder yield 0.100 g; 49% mp 162-163° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 2.81 (1H, dd, J=10.7 Hz, 14.3 Hz), 3.08 (1H, dd, J=4.2 Hz, 14.1 Hz),3.28 (1H, d, J=3.6 Hz), 4.79-4.89 (1H, m), 5.08 (1H, t, J=3.8 Hz), 5.63(1H, s), 5.72 (1H, tt, J=4.0 Hz, 53.4 Hz), 5.89 (1H, s), 7.10 (2H, t,J=8.7 Hz), 7.18-7.32 (7H, m), 7.43-7.50 (3H, m), 7.57 (1H, d, J=8.4 Hz),7.59 (1H, d, J=8.4 Hz), 8.33 (1H, d, J=8.4 Hz); IR (KBr) 3621, 3248,1638, 1541, 1508, 1223, 1101, 789 cm⁻¹

Example 352 tert-butylN-[(1RS,2SR)-2-(3-chlorophenyl)-1-[4-(2,2-difluoro-3-methylbutyl)benzyl]-2-hydroxyethyl]carbamate

1) 3-methyl-1-(4-methylphenyl)butan-2-one

While stirring magnesium (22.5 g, 925 mmol) and iodine (1 crumb) indiethyl ether (400 ml), a solution of 4-methylbenzyl chloride (65.0 g,463 mmol) in diethyl ether (500 ml) was dropwise added slowly at roomtemperature. After completion of the dropwise addition, the mixture wasstirred at room temperature for 0.5 hr. To the reaction solution wasadded dropwise a solution of isobutyronitrile (21.31 g, 308.3 mmol) indiethyl ether (100 ml) under ice-cooling, and the mixture was stirredovernight at room temperature. To the reaction solution was addeddropwise 1N hydrochloric acid under ice-cooling, and the mixture wasstirred at room temperature for 1 hr. The diethyl ether layer wasseparated from the mixture, and the aqueous layer was extracted withdiethyl ether. The recovered organic layer was dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe obtained residue was purified by silica gel column chromatography(hexane/ethyl acetate=15/1−9/1) to give the objective substance.

pale-yellow liquid yield 52.64 g, 97% ¹H-NMR (CDCl₃, 300 MHz) δ 1.09(6H, d, J=6.9 Hz), 2.33 (3H, s), 2.67-2.77 (1H, m), 3.70 (2H, s), 7.08(2H, d, J=8.1 Hz), 7.13 (2H, d, J=7.8 Hz); IR (neat) 2971, 1713, 1514,1464, 1042, 781 cm⁻¹

2) 4-(2,2-difluoro-3-methylbutyl)toluene

A mixture of 3-methyl-1-(4-methylphenyl)butan-2-one (25.00 g, 141.8mmol) and (diethylamino)sulfur trifluoride (25.1 g, 156 mmol) wasstirred overnight at room temperature. The reaction solution was pouredinto ice water, and the mixture was stirred and extracted twice withdiethyl ether. The recovered organic layer was dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe obtained residue was purified by silica gel column chromatography(hexane-hexane/ethyl acetate=20/1) to give the objective substance.

colorless liquid yield 8.562 g, 31% ¹H-NMR (CDCl₃, 300 MHz) 61.04 (6H,d, J=6.9 Hz), 1.91-2.05 (1H, m), 2.33 (3H, s), 3.09 (2H, t, J=17.0 Hz),7.12 (2H, d, J=8.1 Hz), 7.17 (2H, d, J=8.4 Hz); IR (neat) 2975, 1514,999 cm⁻¹

3) tert-butyl(4RS,5SR)-5-(3-chlorophenyl)-4-[4-(2,2-difluoro-3-methylbutyl)benzyl]-2-oxo-1,3-oxazolidine-3-carboxylate

solution of 4-(2,2-difluoro-3-methylbutyl)toluene (4.06 g),N-bromosuccinimide (3.64 g, 20.5 mmol) and 2,2′-azobis(isobutyronitrile)(30 mg) in carbon tetrachloride (30 ml) was heated under reflux for 1.5hrs. After cooling the reaction solution to room temperature, the whiteprecipitate was removed by filtration and washed with hexane. Thesolvent of the recovered filtrate was evaporated under reduced pressureto give a yellow liquid.

To a solution of ethyl (3-chlorobenzoyl)acetate (4.64 g, 20.5 mmol) in1,2-dimethoxyethane (40 ml) was added a suspension (0.82 g, 20.5 mmol)of 60% sodium hydride in liquid paraffin under ice-cooling, and themixture was stirred as it was for 0.5 hr. A solution of the liquidobtained above in 1,2-dimethoxyethane (20 ml) was added thereto at roomtemperature, and the mixture was stirred overnight at room temperature.The reaction solution was poured into water, and extracted twice withethyl acetate. The recovered organic layer was dried over anhydrousmagnesium sulfate and the solvent was evaporated under reduced pressure.The obtained residue was passed through silica gel column chromatography(hexane/ethyl acetate=15/1−9/1) to give a crude product of ethyl3-(3-chlorophenyl)-2-[4-(2,2-difluoro-3-methylbutyl)benzyl]-3-oxopropionateas a yellow liquid.

While stirring zinc chloride (2.49 g, 18.3 mmol) in diethyl ether (30ml), sodium borohydride (1.38 g, 36.6 mmol) was added at roomtemperature, and the mixture was stirred as it was for 2 hrs. Theinsoluble material in the mixture was removed by filtration and washedwith diethyl ether to give a solution of zinc borohydride in diethylether. To the obtained solution was added a solution of the liquidobtained above in diethyl ether (20 ml) under ice-cooling, and themixture was stirred as it was for 20 min. To the reaction solution wasadded dilute hydrochloric acid by small portions to decompose excesszinc borohydride, and the mixture was extracted twice with ethylacetate. The recovered organic layer was dried over anhydrous magnesiumsulfate and the solvent was evaporated under reduced pressure. Theobtained residue was passed through silica gel column chromatography(hexane/ethyl acetate=9/1−6/1) to give a crude product of ethyl(2RS,3RS)-3-(3-chlorophenyl)-2-[4-(2,2-difluoro-3-methylbutyl)benzyl]-3-hydroxypropionateas a yellow liquid.

A mixture of the liquid obtained above, 1N aqueous sodium hydroxidesolution (9.26 ml, 9.26 mmol), methanol (20 ml) and tetrahydrofuran (20ml) was stirred overnight at room temperature. The reaction solution wasconcentrated, diluted with water, acidified with hydrochloric acid, andextracted twice with ethyl acetate. The recovered organic layer wasdried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure to give a crude product of(2RS,3RS)-3-(3-chlorophenyl)-2-[4-(2,2-difluoro-3-methylbutyl)benzyl]-3-hydroxypropionicacid as a yellow solid.

To a solution of the solid obtained above in tetrahydrofuran (40 ml)were added triethylamine (0.77 ml, 5.56 mmol) and diphenylphosphorylazide (1.40 g, 5.09 mmol), and the mixture was stirred at 65° C.overnight. The solvent of the reaction solution was evaporated underreduced pressure and the obtained residue was passed through silica gelcolumn chromatography (hexane/ethyl acetate=3/1−1/1) to give a crudeproduct of(4RS,5SR)-5-(3-chlorophenyl)-4-[4-(2,2-difluoro-3-methylbutyl)benzyl]-1,3-oxazolidin-2-oneas a white solid.

A solution of the solid obtained above, di-tert-butyl dicarbonate (0.69g, 3.18 mmol) and 4-N,N-dimethylaminopyridine (32 mg, 0.27 mmol) inacetonitrile (30 ml) was stirred overnight at room temperature. Thesolvent of the reaction solution was evaporated under reduced pressureand the obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate=9/1−6/1) to give the objectivesubstance.

pale-yellow liquid yield 0.684 g, 7% ¹H-NMR (CDCl₃, 300 MHz) δ 1.03 (6H,d, J=6.9 Hz), 1.49 (9H, s), 1.88-2.02 (1H, m), 2.57 (1H, dd, J=8.7 Hz,14.1 Hz), 2.86 (1H, dd, J=4.7 Hz, 14.3 Hz), 3.02 (2H, t, J=17.3 Hz),4.82 (1H, ddd, J=4.9 Hz, 7.1 Hz, 8.5 Hz), 5.64 (1H, d, J=7.2 Hz), 6.63(2H, d, J=7.8 Hz), 6.99-7.05 (3H, m), 7.15-7.20 (2H, m), 7.27 (1H, d,J=8.1 Hz); IR (neat) 2980, 1809, 1728, 1360, 1312, 1155, 1071, 733 cm⁻¹

4) tert-butylN-[(1RS,2SR)-2-(3-chlorophenyl)-1-[4-(2,2-difluoro-3-methylbutyl)benzyl]-2-hydroxyethyl]carbamate

To a solution of tert-butyl(4RS,5SR)-5-(3-chlorophenyl)-4-[4-(2,2-difluoro-3-methylbutyl)benzyl]-2-oxo-1,3-oxazolidine-3-carboxylate(0.684 g, 1.385 mmol) in tetrahydrofuran (20 ml) was added a solution ofsodium hydroxide (58 mg, 1.45 mmol) in methanol (2 ml) underice-cooling, and the mixture was stirred as it was for 0.5 hr. Thereaction solution was diluted with ethyl acetate, washed with water,dried over anhydrous magnesium sulfate and passed through silica gel.The solvent was evaporated under reduced pressure and the obtainedresidue was crystallized from ethyl acetate-diisopropyl ether-hexane togive the objective substance.

white powder yield 0.524 g, 81% mp 139-141° C.; ¹H-NMR (CDCl₃, 200 MHz)δ 1.03 (6H, d, J=6.8 Hz), 1.37 (9H, s), 1.85-2.06 (1H, m), 2.64 (1H, dd,J=10.2 Hz, 14.6 Hz), 2.75 (1H, dd, J=5.4 Hz, 14.6 Hz), 3.09 (2H, t,J=17.0 Hz), 3.63 (1H, br s), 4.12 (1H, br s), 4.53 (1H, br d, J=6.2 Hz),4.91 (1H, br s), 7.07 (2H, d, J=8.0 Hz), 7.19 (2H, d, J=8.0 Hz), 7.28(3H, s), 7.41 (1H, s); IR (KBr) 3358, 2984, 1682, 1530, 1167, 1009 cm⁻¹;Anal. Calcd for C₂₅H₃₂ClF₂NO₃: C, 64.16; H, 6.89; N, 2.99. Found: C,64.21; H, 6.90; N, 3.01.

Example 353N-[(1RS,2SR)-2-(3-chlorophenyl)-1-[4-(2,2-difluoro-3-methylbutyl)benzyl]-2-hydroxyethyl]-4-fluoronaphthalene-1-carboxamide

A solution of tert-butylN-[(1RS,2SR)-2-(3-chlorophenyl)-1-[4-(2,2-difluoro-3-methylbutyl)benzyl]-2-hydroxyethyl]carbamate(0.200 g, 0.427 mmol) in trifluoroacetic acid (2 ml) was stirred at roomtemperature for 15 min. The reaction solution was evaporated underreduced pressure, diluted with water, alkalified with potassiumcarbonate, and extracted twice with ethyl acetate. The recovered organiclayer was dried over anhydrous sodium sulfate and the solvent wasevaporated under reduced pressure to give as a white solid.

While stirring a solution of the solid obtained above,4-fluoro-1-naphthoate (81 mg, 0.43 mmol) and 1-hydroxybenzotriazolehydrate (65 mg, 0.43 mmol) in acetonitrile (10 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (82 mg, 0.43mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the obtained residue was purified by silica gel columnchromatography (hexane/ethyl acetate=2/1−1/1). Crystallization fromdiisopropyl ether-hexane gave the objective substance.

white crystal yield 0.153 g, 66% mp 181-182° C.; ¹H-NMR (CDCl₃-DMSO-d₆,200 MHz) δ 1.02 (3H, d, J=7.0 Hz), 1.02 (3H, d, J=6.8 Hz), 1.86-2.06(1H, m), 2.80-2.97 (2H, m), 3.09 (2H, t, J=17.2 Hz), 4.68-4.82 (1H, m),5.07 (1H, t, J=4.0 Hz), 5.19 (1H, d, J=3.6 Hz), 6.98-7.37 (9H, m),7.40-7.58 (4H, m), 7.82 (1H, d, J=8.2 Hz), 8.06 (1H, d, J=8.4 Hz); IR(KBr) 3297, 1640, 1534, 1264, 1057, 774, 760 cm⁻¹; Anal. Calcd forC₃₁H₂₉ClF₃NO₂: C, 68.95; H, 5.41; N, 2.59. Found: C, 68.88; H, 5.33; N,2.55.

Example 3545-chloro-N-[(1RS,2SR)-2-(3-chlorophenyl)-1-[4-(2,2-difluoro-3-methylbutyl)benzyl]-2-hydroxyethyl]naphthalene-1-carboxamide

A solution of tert-butylN-[(1RS,2SR)-2-(3-chlorophenyl)-1-[4-(2,2-difluoro-3-methylbutyl)benzyl]-2-hydroxyethyl]carbamate(0.200 g, 0.427 mmol) in trifluoroacetic acid (2 ml) was stirred at roomtemperature for 15 min. The reaction solution was evaporated underreduced pressure, diluted with water, alkalified with potassiumcarbonate, and extracted twice with ethyl acetate. The recovered organiclayer was dried over anhydrous sodium sulfate and the solvent wasevaporated under reduced pressure to give a white solid.

While stirring the solid obtained above, 5-chloro-1-naphthoate (88 mg,0.43 mmol) and 1-hydroxybenzotriazole hydrate (65 mg, 0.43 mmol) inacetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (82 mg, 0.43 mmol) was added, and the mixture was stirredovernight at room temperature. The reaction solution was diluted withethyl acetate, washed with aqueous sodium hydrogen carbonate solutionand dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure and the obtained residue was purified by silicagel column chromatography (hexane/ethyl acetate=2/1−1/1).Crystallization from diisopropyl ether-hexane gave the objectivesubstance.

white crystal yield 0.178 g, 75% mp 170-171° C.; ¹H-NMR (CDCl₃-DMSO-d₆,300 MHz) δ 1.02 (3H, d, J=6.9 Hz), 1.03 (3H, d, J=6.9 Hz), 1.89-2.03(1H, m), 2.86 (1H, dd, J=10.8 Hz, 14.1 Hz), 2.95 (1H, dd, J=4.5 Hz, 14.4Hz), 3.10 (2H, t, J=17.4 Hz), 4.73-4.82 (1H, m), 5.05 (1H, t, J=3.8 Hz),5.19 (1H, d, J=3.9 Hz), 7.16-7.38 (8H, m), 7.44-7.58 (5H, m), 7.64 (1H,d, J=8.7 Hz), 8.29 (1H, d, J=8.7 Hz); IR (KBr) 3272, 1638, 1535, 1202,785 cm⁻¹; Anal. Calcd for C₃₁H₂₉Cl₂F₂NO₂: C, 66.91; H, 5.25; N, 2.52.Found: C, 67.01; H, 5.27; N, 2.41.

Example 3554-fluoro-N-[(1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-[4-(tert-pentyl)benzyl]ethyl]naphthalene-1-carboxamide

1) 4-(tert-pentyl)benzyl alcohol

A solution of tert-pentylbenzene (10.04 g, 67.72 mmol) andhexamethylenetetramine (9.49 g, 67.7 mmol) in trifluoroacetic acid (100ml) was stirred at 90° C. overnight. The reaction solution wasevaporated under reduced pressure, diluted with water, alkalified withpotassium carbonate, and extracted twice with ethyl acetate. Therecovered organic layer was dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure to give a crude product of4-(tert-pentyl)benzaldehyde as a dark brown liquid.

To a solution of the liquid obtained above in methanol (100 ml) wasadded sodium borohydride (1.28 g, 33.9 mmol) by small portions underice-cooling and the mixture was stirred overnight at room temperature.The reaction solution was concentrated, diluted with water, andextracted twice with diethyl ether. The recovered organic layer wasdried over anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate=9/1−6/1) to give the objectivesubstance.

yellow liquid yield 10.83 g, 74% ¹H-NMR (CDCl₃, 300 MHz) δ 0.68 (3H, t,J=7.4 Hz), 1.28 (6H, s), 1.65 (2H, q, J=7.4 Hz), 4.66 (2H, d, J=5.7 Hz),7.30 (2H, d, J=8.4 Hz), 7.33 (2H, d, J=8.7 Hz); IR (neat) 3281, 2965,1462, 1015 cm⁻¹

2) ethyl 3-(3-chlorophenyl)-3-oxo-2-[4-(tert-pentyl)benzyl]propionate

To a solution of 4-(tert-pentyl)benzyl alcohol (4.075 g, 22.86 mmol) andtriethylamine (4.78 ml, 34.3 mmol) in ethyl acetate (50 ml) was addeddropwise a solution of methanesulfonyl chloride (3.14 g, 27.4 mmol) inethyl acetate (10 ml) under ice-cooling, and the mixture was stirred asit as for 10 min. The resulting precipitate was removed by filtrationand washed with diethyl ether. The solvent of the recovered filtrate wasevaporated under reduced pressure to give a crude product ofmethanesulfonic acid ester as a yellow liquid.

To a solution of ethyl (3-chlorobenzoyl)acetate (5.18 g, 22.9 mmol) in1,2-dimethoxyethane (40 ml) was added a suspension (0.91 g, 22.9 mmol)of 60% sodium hydride in liquid paraffin under ice-cooling, and themixture was stirred as it was for 0.5 hr. A solution of methanesulfonicacid ester obtained above in 1,2-dimethoxyethane (20 ml) was addedthereto at room temperature, and the mixture was stirred at 50° C.overnight. The reaction solution was poured into water, andextracted-twice with ethyl acetate. The recovered organic layer wasdried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the obtained residue was purified by silica gelcolumn chromatography (hexane/ethyl acetate=15/1) to give the objectivesubstance.

yellow liquid yield 6.969 g, 79% ¹H-NMR (CDCl₃, 300 MHz) δ 0.62 (3H, t,J=7.4 Hz), 1.12 (3H, t, J=7.2 Hz), 1.23 (6H, s), 1.59 (2H, q, J=7.4 Hz),3.26 (1H, dd, J=7.5 Hz, 14.1 Hz), 3.32 (1H, dd, J=7.2 Hz, 14.4 Hz), 4.10(1H, q, J=7.0 Hz), 4.11 (1H, q, J=7.2 Hz), 4.54 (1H, t, J=7.4 Hz), 7.13(2H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4 Hz), 7.36 (1H, t, J=8.0 Hz), 7.51(1H, dd, J=1.2 Hz, 7.8 Hz), 7.78 (1H, dd, J=1.5 Hz, 7.8 Hz), 7.89 (1H,t, J=1.8 Hz); IR (neat) 2965, 1736, 1692, 1229 cm⁻¹

3) ethyl(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(tert-pentyl)benzyl]propionate

While stirring zinc chloride (4.91 g, 36.0 mmol) in diethyl ether (50ml), sodium borohydride (2.73 g, 72.0 mmol) was added at roomtemperature, and the mixture was stirred as it was for 2 hrs. Insolublematerial in the mixture was removed by filtration and washed withdiethyl ether to give a solution of zinc borohydride in diethyl ether.To the obtained solution was added a solution of ethyl3-(3-chlorophenyl)-3-oxo-2-[4-(tert-pentyl)benzyl]propionate (6.969 g,18.01 mmol) in diethyl ether (30 ml) under ice-cooling, and the mixturewas stirred as it was for 20 min. To the reaction solution was addeddilute hydrochloric acid by small portions to decompose excess zincborohydride, and the mixture was extracted twice with ethyl acetate. Therecovered organic layer was dried over anhydrous magnesium sulfate andthe solvent was evaporated under reduced pressure. The obtained crudeproduct was purified by silica gel column chromatography (hexane/ethylacetate=15/1−6/1) to give the objective substance.

yellow liquid yield 6.751 g, 96%

¹H-NMR (CDCl₃, 200 MHz) δ 0.63 (3H, t, J=7.4 Hz), 0.923 (3H, t, J=7.1Hz), 1.23 (6H, s), 1.59 (2H, q, J=7.4 Hz), 2.84-2.99 (3H, m), 3.13 (1H,d, J=3.0 Hz), 3.90 (1H, q, J=7.2 Hz), 3.91 (1H, q, J=7.4 Hz), 5.02 (1H,t, J=3.1 Hz), 7.00 (2H, d, J=8.0 Hz), 7.18 (2H, d, J=8.0 Hz), 7.26 (3H,s), 7.42 (1H, s); IR (neat) 3480, 2965, 1728, 1715, 1375, 1192, 1159,1032, 789 cm⁻¹

4)(4RS,5SR)-5-(3-chlorophenyl)-4-[4-(tert-pentyl)benzyl]-1,3-oxazolidin-2-one

A mixture of ethyl(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(tert-pentyl)benzyl]propionate(6.650 g, 17.10 mmol), sodium hydroxide (1.37 g, 34.2 mmol), methanol(20 ml), water (20 ml) and tetrahydrofuran (20 ml) was stirred overnightat room temperature. The reaction solution was concentrated, dilutedwith water, acidified with hydrochloric acid, and extracted twice withethyl acetate. The recovered organic layer was dried over anhydroussodium sulfate and the solvent was evaporated under reduced pressure togive a crude product of(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(tert-pentyl)benzyl]propionicacid as a white solid.

To a solution of the solid obtained above in tetrahydrofuran (70 ml)were added triethylamine (2.86 ml, 20.5 mmol) and diphenylphosphorylazide (5.18 g, 18.8 mmol), and the mixture was stirred at 65° C.overnight. The solvent of the reaction solution was evaporated underreduced pressure, and diluted with ethyl acetate. The obtained aqueousethyl acetate solution was washed with water, passed through silica gel,and the solvent was evaporated under reduced pressure. The obtainedcrystals were washed with diisopropyl ether to give the objectivesubstance.

white crystal yield 4.312 g, 71% mp 223-224° C.; ¹H-NMR (CDCl₃-DMSO-d₆,300 MHz) δ 0.65 (3H, t, J=7.4 Hz), 1.24 (6H, s), 1.60 (2H, q, J=7.4 Hz),2.30 (1H, dd, J=6.3 Hz, 14.1 Hz), 2.37 (1H, dd, J=9.0 Hz, 14.4 Hz),4.33-4.41 (1H, m), 5.70 (1H, d, J=7.8 Hz), 6.84-6.87 (3H, m), 7.15-7.23(3H, m), 7.27-7.33 (3H, m); IR (KBr) 3247, 2965, 1738, 1240, 1019 cm⁻¹;Anal. Calcd for C₂₁H₂₄ClNO₂: C, 70.48; H, 6.76; N, 3.91. Found: C,70.35; H, 6.59; N, 3.77.

5)(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(tert-pentyl)phenyl]propan-1-ol

(4RS,5SR)-5-(3-chlorophenyl)-4-[4-(tert-pentyl)benzyl]-1,3-oxazolidin-2-one(4.046 g, 11.31 mmol) and sodium hydroxide (1.81 g, 45.2 mmol) wereheated under reflux in ethanol (40 ml)-water (2 ml) for 5 hrs. Thereaction solution was diluted with water, and the mixture was stirred asit was for 0.5 hr. The recovered precipitate was washed with water anddiisopropyl ether-hexane to give the objective substance.

white crystal yield 2.833 g, 76% mp 86-87° C.; ¹H-NMR (CDCl₃, 200 MHz) δ0.66 (3H, t, J=7.3 Hz), 1.26 (6H, s), 1.61 (2H, a, J=7.4 Hz), 2.30 (1H,dd, J=10.2 Hz, 14.0 Hz), 2.72 (1H, dd, J=3.2 Hz, 13.6 Hz), 3.30 (1H,ddd, J=3.5 Hz, 4.7 Hz, 10.4 Hz), 4.67 (1H, d, J=4.8 Hz), 7.05 (2H, d,J=8.4 Hz), 7.22-7.30 (5H, m), 7.42 (1H, s); IR (KBr) 3400-2700, 1576,1474, 1460, 1420, 1044, 781 cm⁻¹; Anal. Calcd for C₂₀H₂₆ClNO.0.1H₂O: C,71.99; H, 7.91; N, 4.20. Found: C, 71.96; H, 7.85; N, 4.14.

6)4-fluoro-N-[(1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-[4-(tert-pentyl)benzyl]ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(tert-pentyl)phenyl]propan-1-ol(0.300 g, 0.904 mmol), 4-fluoro-1-naphthoic acid (0.17 g, 0.90 mmol) and1-hydroxybenzotriazole hydrate (0.14 g, 0.90 mmol) in acetonitrile (10ml)-N,N-dimethylformamide (2 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 g,0.90 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-diisopropyl ether-hexane to give theobjective substance.

white amorphous powder yield 0.381 g, 84% ¹H-NMR (CDCl₃-DMSO-d₆, 300MHz) δ 0.64 (3H, t, J=7.5 Hz), 1.25 (6H, s), 1.61 (2H, q, J=7.5 Hz),2.84 (1H, dd, J=10.5 Hz, 14.4 Hz), 2.93 (1H, dd, J=4.2 Hz, 14.4 Hz),4.72-4.81 (1H, m), 5.05 (1H, t, J=3.6 Hz), 5.28 (1H, d, J=3.6 Hz), 7.00(1H, dd, J=8.1 Hz, 10.2 Hz), 7.12-7.35 (8H, m), 7.41-7.58 (4H, m), 7.82(1H, d, J=8.1 Hz), 8.05 (1H, d, J=8.1 Hz); IR (KBr) 3414, 3250, 2965,1638, 1628, 1599, 1514, 1262, 1233, 766 cm⁻¹; Anal. Calcd forC₃₁H₃₁ClFNO₂: C, 73.87; H, 6.20; N, 2.78. Found: C, 73.53; H, 6.13; N,2.84.

Example 3565-chloro-N-[(1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-[4-(tert-pentyl)benzyl]ethyl]naphthalene-1-carboxamide

While stirring(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(tert-pentyl)phenyl]propan-1-ol(0.300 g, 0.904 mmol), 5-chloro-1-naphthoic acid (0.19 g, 0.90 mmol) and1-hydroxybenzotriazole hydrate (0.14 g, 0.90 mmol) in acetonitrile (10ml)-N,N-dimethylformamide (2 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 g,0.90 mmol) was added, and the mixture was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure and the obtained residue wascrystallized from ethyl acetate-diisopropyl ether-hexane to give theobjective substance.

white amorphous powder yield 0.363 g, 77% ¹H-NMR (CDCl₃-DMSO-d₆, 300MHz) δ 0.64 (3H, t, J=7.4 Hz), 1.26 (6H, s), 1.62 (2H, q, J=7.4 Hz),2.83 (1H, dd, J=11.0 Hz, 14.6 Hz), 2.95 (1H, dd, J=4.2 Hz, 14.7 Hz),4.73-4.82 (1H, m), 5.03 (1H, t, J=3.9 Hz), 5.26 (1H, d, J=3.9 Hz), 7.16(2H, d, J=8.4 Hz), 7.22-7.36 (7H, m), 7.42-7.49 (2H, m), 7.55 (1H, d,J=7.5 Hz), 7.58 (1H, s), 7.65 (1H, d, J=8.4 Hz), 8.28 (1H, d, J=8.7 Hz);IR (KBr) 3262, 2963, 1636, 1516, 785 cm⁻¹; Anal. Calcd for C₃₁H₃₁Cl₂NO₂:C, 71.54; H, 6.00; N, 2.69. Found: C, 71.24; H, 6.11; N, 2.42.

Example 357N-[(1RS,2SR)-1-(4-tert-butylbenzyl)-2-(4-fluorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide

1) ethyl 2-[4-(tert-butyl)benzyl]-3-(4-fluorophenyl)-3-oxopropionate

To a solution of p-tert-butylbenzyl alcohol (5 ml, 28.2 mmol) in ethylacetate (60 ml) was added triethylamine (5.9 ml, 42.3 mmol) andmethanesulfonyl chloride (2.4 ml, 31.0 mmol) was added underice-cooling. The mixture was stirred as it was for 1 hr. Theprecipitated crystals were filtered, and concentrated to give mesylate,which was used as it was in the next reaction.

A solution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (5.68 g, 27 mmol)in dimethoxyethane (50 ml) was ice-cooled and sodium hydride (60%, 1.13g, 28 mmol) was added. The mixture was stirred under ice-cooling for 30min. A solution of the mesylate in dimethoxyethane (30 ml) was addedthereto, and the mixture was stirred at room temperature for 1 hr. Aftercompletion of the reaction, 1N hydrochloric acid was added to quench thereaction. The mixture was extracted with ethyl acetate, dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=10:1, 8:1) to give ethyl2-[4-(tert-butyl)benzyl]-3-(4-fluorophenyl)-3-oxopropionate (8.97 g,93%) as a colorless transparent oil.

IR ν max^(KBr) (cm⁻¹): 1736, 1685, 1599, 1508, 1267, 1234, 1159 ¹H-NMR(CDCl₃)δ (ppm) 1.11 (3H, t, J=4.8 Hz), 1.27 (9H, s) 3.28 (1H, dd, J=2.0,4.8 Hz), 4.10 (2H, q, J=4.8 Hz), 4.56 (1H, t, J=4.8 Hz), 7.07-7.15 (4H,m), 7.27 (2H, d, J=5.4 Hz), 7.95-8.00 (2H, m).

2) ethyl(2RS,3RS)-2-[4-(tert-butyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionate

To a suspension (80 ml) of zinc chloride (6.59 g, 48.3 mol) in ether wasadded sodium borohydride (3.66 g, 96.6 mol) at room temperature and themixture was stirred as it as for 2 hrs. A solution of ethyl2-[4-(tert-butyl)benzyl]-3-(4-fluorophenyl)-3-oxopropionate (8.61 g,24.15 mmol) in ether (40 ml) was added, and the mixture was stirred atroom temperature for 15 min. The reaction was stopped with 1Nhydrochloric acid, and the reaction solution was diluted with ethylacetate, washed with water, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=8:1,5:1) to give ethyl(2RS,3RS)-2-[4-(tert-butyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionate(8.00 g, 92%) as a colorless transparent oil.

IR ν max^(KBr) (cm⁻¹): 3452, 1726, 1604, 1510, 1464, 1394, 1373, 1224,1157, 1030 ¹H-NMR (CDCl₃) δ (ppm) 0.89 (3H, t, J=7.4 Hz), 1.27 (9H, s)2.95 (2H, s) 3.04 (1H, d, J=3.0 Hz), 3.87-3.95 (2H, m), 4.99 (1H, s)6.97-7.07 (4H, m), 7.21-7.28 (2H, m), 7.32-7.39 (2H, m).

3)(2RS,3RS)-2-[4-(tert-butyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionicacid

To a solution of ethyl2-[4-(tert-butyl)benzyl]-3-(4-fluorophenyl)-3-oxopropionate (7.43 g,20.7 mmol) in tetrahydrofuran-methanol (20 ml-20 ml) was added sodiumhydroxide at room temperature, and the mixture was stirred overnight atroom temperature. After completion of the reaction, the organic solventwas evaporated under reduced pressure, and the residue was acidifiedwith 1N hydrochloric acid and extracted with ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. Recrystallization from hexane-ethylacetate gave(2RS,3RS)-2-[4-(tert-butyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionicacid (5.51 g, 81%) as colorless crystals.

mp 102-104° C. IR ν max^(KBr) (cm⁻¹): 2500-3300, 1709, 1606, 1510, 1226,1159, 839 ¹H-NMR (CDCl₃) δ (ppm) 1.27 (9H, s) 2.85-3.02 (3H, m), 5.04(1H, d, J=4.4 Hz), 6.98-7.06 (4H, m), 7.22-7.27 (2H, m), 7.31-7.38 (2H,m).

4)(4RS,5SR)-4-[4-(tert-butyl)benzyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-2-[4-(tert-butyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionicacid (5.07 g, 15.3 mmol) in tetrahydrofuran (150 ml) were addedtriethylamine (3.2 ml, 22.95 mmol) and diphenylphosphoryl azide (3.63ml, 16.8 mmol) at room temperature, and the mixture was heated underreflux for 5 hrs. The solvent was evaporated, passed through silica gelcolumn, and purified by recrystallization (hexane-ethyl acetate) to give(4RS,5SR)-4-[4-(tert-butyl)benzyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one(3.98 g, 79%) as colorless crystals.

mp 218-219° C. IR ν max^(KBr) (cm⁻¹): 3284, 1736, 1610, 1514, 1363, 1230¹H-NMR (CDCl₃) δ (ppm) 1.28 (9H, s) 2.10-2.86 (2H, m), 4.15-4.26 (1H,m), 4.95 (1H, s) 5.78 (1H, d, J=7.6 Hz), 6.95 (2H, d, J=8.4 Hz),7.08-7.18 (2H, m), 7.26-7.40 (4H, m).

5)(1RS,2RS)-2-amino-3-[4-(tert-butyl)benzyl]-1-(4-fluorophenyl)propan-1-ol

To a solution of(4RS,5SR)-4-[4-(tert-butyl)benzyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one(3.80 g, 11.6 mmol) in ethanol was added 8N aqueous sodium hydroxidesolution (7.3 ml, 58.4 mmol), and the mixture was heated under refluxfor 5 hrs. After completion of the reaction, the reaction solution wasdiluted with water, and extracted with ethyl acetate. The organic layerswere combined, washed with saturated brine, dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by recrystallization (hexane-ethyl acetate) to give(1RS,2RS)-2-amino-3-[4-(tert-butyl)benzyl]-1-(4-fluorophenyl)propan-1-ol(2.57 g, 74%) as colorless crystals.

mp 139-140° C. IR ν max^(KBr) (cm⁻¹): 2500-3300, 1603, 1508, 1363, 1224,1155, 1043 ¹H-NMR (CDCl₃) δ (ppm) 1.29 (9H, s) 2.06 (2H, br) 2.30 (1H,dd, J=10.4, 13.6 Hz), 2.72 (1H, dd, J=3.4, 14.0 Hz), 3.26 (1H, ddd,J=3.8, 4.8, 10.6 Hz), 4.69 (1H, d, J=4.8 Hz), 7.01-7.10 (4H, m),7.25-7.40 (4H, m).

6)N-[(1RS,2SR)-1-(4-tert-butylbenzyl)-2-(4-fluorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide

To a solution of(1RS,2RS)-2-amino-3-[4-(tert-butyl)benzyl]-1-(4-fluorophenyl)propan-1-ol(0.30 g, 0.998 mmol) in acetonitrile (10 ml) were added4-fluoronaphthalene-1-carboxylic acid (0.20 g, 1.05 mmol) and1-hydroxybenzotriazole monohydrate (0.16 g, 1.05 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g,1.05 mmol) was finally added. The mixture was stirred at roomtemperature for 12 hrs. The mixture was diluted with ethyl acetate,washed with saturated aqueous sodium hydrogen carbonate, water andsaturated brine, dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=5:1, 3:1).

Recrystallization (hexane-ethyl acetate) gaveN-[(1RS,2SR)-1-(4-tert-butylbenzyl)-2-(4-fluorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide(0.30 g, 64%) as colorless crystals.

mp 149-150° C. elemental analysis C₃₀H₂₉NO₂F₂ Calculated: C, 76.09; H,6.17; N, 2.96. Found: C, 76.07; H, 6.09; N, 2.92. IR ν max^(KBr)(cm⁻¹):3263, 1639, 1601, 1510, 1263, 1226, 1051, 835 ¹H-NMR (CDCl₃) δ (ppm)1.31 (9H, s) 2.72 (1H, dd, J=10.6, 14.4 Hz) 3.03 (1H, dd, J=4.4, 14.2Hz), 4.70-4.84 (1H, m), 5.04-5.08 (1H, m), 5.83 (1H, d, J=8.0 Hz),6.90-7.15 (6H, m), 7.31-7.57 (6H, m), 7.85 (1H, d, J=8.0 Hz), 8.97 (1H,d, J=7.6 Hz).

Example 358N-[(1RS,2SR)-1-(4-tert-butylbenzyl)-2-(4-fluorophenyl)-2-hydroxyethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution of(1RS,2RS)-2-amino-3-[4-(tert-butyl)benzyl]-1-(4-fluorophenyl)propan-1-ol(0.41 g, 1.36 mmol) in acetonitrile (10 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (0.20 g, 1.05mmol) and 1-hydroxybenzotriazole monohydrate (0.16 g, 1.05 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g,1.05 mmol) was finally added. The mixture was stirred at roomtemperature for 3 days. The mixture was diluted with ethyl acetate,washed with saturated aqueous sodium hydrogen carbonate solution, waterand saturated brine, dried over anhydrous magnesium sulfate, filteredand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate=5:1, 2:1).Recrystallization (hexane-ethyl acetate) gaveN-[(1RS,2SR)-1-(4-tert-butylbenzyl)-2-(4-fluorophenyl)-2-hydroxyethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.43 g, 67%) as colorless crystals.

mp 140-142° C. elemental analysis C₃₁H₃₄NO₂.0.25H₂O Calculated: C,78.20; H, 7.30; N, 2.94. Found: C; 78.16; H, 7.20; N, 2.86. IR νmax^(KBr) (cm⁻¹): 1637, 1508, 1363, 1222, 1155 ⁻¹H-NMR (CDCl₃)δ (ppm)1.29 (9H, s) 1.96-2.04 (2H, m), 2.13-2.23 (2H, m), 2.62-2.73 (3H, m),2.96 (1H, dd, J=4.4, 14.6 Hz), 4.17 (1H, d, J=3.2 Hz), 4.99-5.01 (1H,m), 5.63 (1H, d, J=7.6 Hz) 5.90 (1H, dt, J=5.6, 11.4 Hz), 6.24 (1H, d,J=11.8 Hz), 6.87 (1H, d, J=1.0 Hz), 7.01-7.16 (5H, m), 7.25-7.33 (3H,m), 7.38-7.45 (2H, m).

Example 359N-[(1RS,2SR)-1-[3-(1,1-difluoroethyl)benzyl]-2-(4-fluorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide

1) 3-(1,1-difluoroethyl)benzonitrile.

To a round-bottomed flask containing 3-acetylbenzophenone (5.81 g, 40.0mmol) was dropwise added bis(2-methoxyethyl)aminosulfur trifluoride(12.5 ml, 67.8 mmol) and ethanol (0.46 ml, 8.14 mmol) was dropwise addedslowly. The mixture was stirred at 80 to 85° C. overnight. The reactionmixture was poured into saturated aqueous sodium hydrogen carbonatesolution, and the mixture was extracted with ether. After drying overanhydrous magnesium sulfate, the residue was filtered and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane:ether=10:1, 8:1, 5:1) to give3-(1,1-difluoroethyl)benzonitrile (5.16 g, 77%) as a colorlesstransparent oil.

IR ν max^(KBr) (cm⁻¹): 2223, 1485, 1429, 1386, 1304, 1186 ¹H-NMR (CDCl₃)δ (ppm) 1.93 (3H, t, J=18.3 Hz), 7.55-7.60 (1H, m) 7.72-7.80 (3H, m).

2) 3-(1,1-difluoroethyl)benzoic acid

To a suspension (100 ml) of 3-(1,1-difluoroethyl)benzonitrile (5.10 g,30.5 mmol) in water was added sodium hydroxide (3.05 g, 76.25 mmol), andthe mixture was stirred at 100° C. for 5 hrs. After completion of thereaction, the reaction solution was acidified with 6N hydrochloric acidand extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure to give 3-(1,1-difluoroethyl)benzoicacid (5.10 g, 90%) as colorless crystals.

mp 96-97° C. IR ν max^(KBr) (cm⁻¹): 2500-3300, 1689, 1616, 1423, 1385,1323, 1278, 1263, 1176 1H-NMR (CDCl₃) δ (ppm): 1.97 (3H, t, J=18.4 Hz),7.52-7.65 (1H, m) 7.76-7.79 (1H, m), 8.17-8.34 (2H, m).

3) 3-(1,1-difluoroethyl)benzyl alcohol

To a suspension (100 ml) of lithium aluminum hydride (2.24 g, 54.4 mmol)in ether was added dropwise a solution of3-(1,1-difluoroethyl)benzonitrile (5.48 g, 29.4 mmol) in ether (50 ml)under ice-cooling, and the mixture was stirred at room temperature for 4hrs. After completion of the reaction, water (2.24 ml), 15% aqueoussodium hydroxide solution (2.24 ml) and water (6.72 ml) weresuccessively added dropwise under ice-cooling. The obtained solid wasfiltered with celite and washed with ethyl acetate. The filtrate wasconcentrated, and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=3:1, 1:1) to give3-(1,1-difluoroethyl)benzyl alcohol (3.82 g, 75%) to give a colorlesstransparent oil.

IR ν max^(KBr) (cm⁻¹): 3292, 1439, 1389, 1305, 1180, 1143 ¹H-NMR (CDCl₃)δ (ppm) 1.91 (3H, t, J=17.8 Hz), 2.08 (1H, s) 4.71 (2H, s) 7.41-7.44(3H, m), 7.50 (1H, s).

4) ethyl2-[3-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-oxopropionate

To a solution of 3-(1,1-difluoroethyl)benzyl alcohol (3.71 ml, 21.5mmol) in ethyl acetate (50 ml) was added triethylamine (4.5 ml, 32.25mmol). To the mixture was added dropwise methanesulfonyl chloride (1.83ml, 23.6 mmol) under ice-cooling, and the mixture was stirred as it wasfor 45 min. The precipitated crystals were filtered, and the filtratewas concentrated to give mesylate, which was directly used in the nextreaction.

A solution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (4.52 g, 21.5mmol) in dimethoxyethane (50 ml) was ice-cooled, and sodium hydride(60%, 0.86 g, 21.5 mmol) was added thereto and the mixture was stirredfor 30 min under ice-cooling. A solution of the mesylate indimethoxyethane (50 ml) was added thereto, and the mixture was stirredovernight at room temperature. After completion of the reaction, thereaction was quenched with 1N hydrochloric acid, and the mixture wasdiluted with ethyl acetate, washed with water and saturated brine, driedover anhydrous magnesium sulfate and filtered. The filtrate wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (hexane:ethyl acetate=8:1, 5:1) to giveethyl 2-[3-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-oxopropionate(7.31 g, 93%) as a colorless transparent oil.

IR ν max^(KBr) (cm⁻¹): 1736, 1685, 1508, 1446, 1385, 1304, 1234, 1159¹H-NMR (CDCl₃) δ (ppm) 1.12 (3H, t, J=7.2 Hz), 1.86 (3H, t, J=18.3 Hz),3.35 (2H, dd, J=2.7, 7.2 Hz), 4.10 (2H, q, J=7.2 Hz) 4.57 (1H, t, J=7.5Hz), 7.08-7.15 (2H, m), 7.26-7.35 (4H, m) 7.96-8.01 (2H, m).

5) ethyl(2RS,3RS)-2-[3-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionate

To a suspension (40 ml) of zinc chloride (5.35 g, 39.2 mmol) in etherwas added sodium borohydride (2.97 g, 78.4 mmol) at room temperature,and the mixture was stirred as it was for 2 hrs. Insoluble material wasfiltered off. To the filtrate was added a solution of ethyl2-[3-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-oxopropionate (7.16g, 19.6 mmol) in ether (40 ml), and the mixture was stirred at roomtemperature for 1.5 hrs. The reaction was quenched with 1N hydrochloricacid, and the mixture was diluted with ethyl acetate and washed withwater and saturated brine. The mixture was dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=8:1, 4:1) to give ethyl(2RS,3RS)-2-[3-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionate(6.24 g, 87%) as a colorless transparent oil.

IR ν max^(KBr) (cm⁻¹): 1728, 1604, 1510, 1446, 1385, 1304 ¹H-NMR (CDCl₃)δ (ppm) 0.91 (3H, t, J=7.4 Hz), 1.87 (3H, t, J=17.6 Hz), 2.90-3.05 (4H,m), 3.87 (1H, q, J=7.8 Hz), 4.99-5.02 (1H, m), 6.98-7.40 (8H, m).

6)(2RS,3RS)-2-[3-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionicacid

To a solution of ethyl(2RS,3RS)-2-[3-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionate(5.97 g, 17.6 mmol) in tetrahydrofuran-ethanol (30 ml)-(20 ml) was added2N sodium hydroxide (18 ml, 36 mmol) at room temperature, and themixture was stirred overnight at room temperature. After completion ofthe reaction, the organic solvent was evaporated under reduced pressure,and the aqueous layer was acidified with 1N hydrochloric acid. Themixture was extracted with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The filtrate was recrystallized from hexane-ethylacetate to give(2RS,3RS)-2-[3-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionicacid(4.48 g, 82%) as colorless crystals.

mp 132-133° C. IR ν max^(KBr) (cm⁻¹): 2800-3300, 1709, 1606, 1512, 1385,1304, 1226, 1178 ¹H-NMR (CDCl₃) δ (ppm) 1.85 (3H, t, J=18.2 Hz), 3.01(3H, m), 5.06 (1H, s) 6.99-7.39 (8H, m).

7)(4RS,5SR)-4-[3-(1,1-difluoroethyl)benzyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-2-[3-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionicacid (4.22 g, 13.6 mmol) in tetrahydrofuran (130 ml) were addedtriethylamine (2.85 ml, 20.4 mmol) and diphenylphosphoryl azide (3.23ml, 14.96 mmol), and the mixture was heated under reflux for 5 hrs. Thesolvent was evaporated, and the residue was diluted with ethyl acetate,washed with water, saturated aqueous sodium hydrogen carbonate andsaturated brine. The organic layer was dried over anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas recrystallized from hexane-ethyl acetate to give[4RS,5SR]-4-(3-[1,1-difluoroethyl)benzyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one(3.99 g, 95%) as colorless crystals.

mp 143-144° C. IR ν max^(KBr) (cm⁻¹): 3231, 1763, 1608, 1512, 1386,1300, 1230 ¹H-NMR (CDCl₃) δ (ppm) 1.88 (3H, t, J=18.4 Hz), 2.29-2.38(2H, m) 4.22-4.33 (1H, m), 5.17 (1H, s) 5.79 (1H, d, J=8.0 Hz) 7.06-7.18(4H, m), 7.29-7.39 (4H, m).

8)(1RS,2SR)-2-amino-3-[3-(1,1-difluoroethyl)phenyl]-1-(4-fluorophenyl)-1-propanol

To a solution of(4RS,5SR)-4-[3-(1,1-difluoroethyl)benzyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one(3.83 g, 12.5 mmol) in ethanol (100 ml) was added 8N aqueous sodiumhydroxide solution (7.8 ml, 39.0 mmol), and the mixture was heated underreflux for 5 hrs. After completion of the reaction, the mixture wasdiluted with water, and extracted with ethyl acetate. The organic layerswere combined, washed with saturated brine, dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue was recrystallized from (hexane-ethyl acetate) to give(1RS,2SR)-2-amino-3-[3-(1,1-difluoroethyl)phenyl]-1-(4-fluorophenyl)-1-propanol(3.08 g, 88%) as colorless crystals.

mp 101-102° C. IR ν max^(KBr) (cm⁻¹): 3363, 1604, 1508, 1448, 1385,1302, 1224, 1176 ¹H-NMR (CDCl₃) δ (ppm) 1.89 (3H, t, J=18.4 Hz), 2.39(1H, dd, J=10.4, 13.6 Hz), 2.82 (1H, dd, J=3.0, 13.6 Hz), 3.25-3.34 (1H,m), 4.69 (1H, d, J=5.0 Hz), 7.03-7.11 (2H, m), 7.11-7.21 (1H, m),7.26-7.41 (5H, m).

9)N-[(1RS,2SR)-1-[3-(1,1-difluoroethyl)benzyl]-2-(4-fluorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide

To a solution of(1RS,2SR)-2-amino-3-[3-(1,1-difluoroethyl)phenyl]-1-(4-fluorophenyl)-1-propanol(0.40 g, 1.42 mmol) in acetonitrile (10 ml) were added4-fluoronaphthalene-1-carboxylic acid (0.283 g, 1.49 mmol) and1-hydroxybenzotriazole monohydrate (0.22 g, 1.49 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g,1.49 mmol) was finally added. The mixture was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate,washed with saturated aqueous sodium hydrogen carbonate solution, waterand saturated brine, dried over anhydrous magnesium sulfate, filteredand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate=5:1, 2:1) andrecrystallization (hexane-ethyl acetate) to giveN-[(1RS,2SR)-1-[3-(1,1-difluoroethyl)benzyl]-2-(4-fluorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide(0.52 g, 81%) as colorless crystals.

mp 182-183° C. Elemental analysis for C₂₈H₂₃NO₂F₄ Calcd: C, 69.85; H,4.81; N, 2.91. Found: C, 69.86; H, 4.75; N, 2.74. IR ν max^(KBr) (cm⁻¹):3277, 1641, 1626, 1601, 1512, 1425, 1307, 1230 ¹H-NMR (CDCl₃) δ (ppm)1.84 (3H, t, J=18.0 Hz), 2.84 (1H, dd, J=10.2, 14.1 Hz), 3.07 (1H, dd,J=4.2, 14.7 Hz), 3.55 (1H, s) 4.72-4.81 (1H, m), 5.08 (1H, s) 5.92 (1H,d, J=8.7 Hz) 6.98 (1H, dd, J=8.1, 9.9 Hz), 7.05-7.15 (3H, m), 7.27-7.48(7H, m) 7.50-7.55 (1H, m), 7.75 (1H, d, J=8.7 Hz), 8.07 (1H, d, J=8.7Hz).

Example 360N-[(1RS,2SR)-1-[3-(1,1-difluoroethyl)benzyl]-2-(4-fluorophenyl)-2-hydroxyethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-3-[3-(1,1-difluoroethyl)phenyl]-1-(4-fluorophenyl)-1-propanol(0.40 g, 1.42 mmol) in acetonitrile (10 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (0.28 g, 1.49mmol) and 1-hydroxybenzotriazole monohydrate (0.22 g, 1.49 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g,1.49 mmol) was finally added. The mixture was stirred overnight at roomtemperature. The mixture was diluted with ethyl acetate, washed withsaturated aqueous sodium hydrogen carbonate, water and saturated brine,dried over anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=5:1, 2:1) and recrystallization(hexane-ethyl acetate) to giveN-[(1RS,2SR)-1-[3-(1,1-difluoroethyl)benzyl]-2-(4-fluorophenyl)-2-hydroxyethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.50 g, 78%) as colorless crystals.

mp 170-171° C. IR ν max^(KBr) (cm⁻¹): 1639, 1510, 1448, 1385, 1305,1222, 1174, 1086 Elemental analysis for C₂₉H₂₈NO₂F₃ Calcd: C, 72.64; H,5.89; N, 2.92. Found: C, 72.61; H, 5.91; N, 2.65. ¹H-NMR (CDCl₃) δ (ppm)1.87 (3H, t, J=18.3 Hz), 1.96-2.04 (2H, m) 2.15-2.21 (2H, m), 2.63-2.67(2H, m), 2.78 (1H, dd, J=10.8, 14.4 Hz), 3.01 (1H, dd, J=4.5, 14.7 Hz),3.70 (1H, d, J=3.3 Hz) 4.65-4.72 (1H, m), 5.03 (1H, t, J=3.9 Hz), 5.72(1H, d, J=7.8 Hz), 5.90 (1H, dt, J=5.1, 12.0 Hz), 6.16 (1H, d, J=11.7Hz), 6.93 (1H, dd, J=1.2, 7.5 Hz), 7.04-7.15 (4H, m), 7.25-7.31 (2H, m),7.34-7.38 (2H, m), 7.41-7.46 (2H, m).

Example 361 tert-butyl(1RS,2RS)-2-hydroxy-2-(2-phenyl-1,3-thiazol-4-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate

1) ethyl 3-oxo-3-(2-phenyl-1,3-thiazol-4-yl)propionate

To a solution of 2-phenyl-1,3-thiazole-4-carboxylic acid (1 g, 4.87mmol) in tetrahydrofuran (10 ml) was added N,N′-carbonyldiimidazole(0.87 g, 5.37 mmol), and the mixture was stirred at room temperature for3 hrs to give an imidazolide solution. A round-bottomed flask preparedseparately, was charged with a solution of ethyl hydrogen malonate (0.78g, 5.84 mmol) in tetrahydrofuran (10 ml), and magnesium ethoxide (0.34g, 2.92 mmol) was added. The mixture was stirred at room temperature for1 hr, and the solvent was concentrated under reduced pressure to give apale-yellow amorphous powder. The imidazolide solution prepared as abovewas added dropwise, and the mixture was stirred overnight at roomtemperature. The mixture was diluted with ethyl acetate, washed with 1Mpotassium hydrogen sulfate, saturated aqueous sodium hydrogen carbonate,water and saturated brine, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=4:1)to give ethyl 3-oxo-3-(2-phenyl-1,3-thiazol-4-yl)propionate (1.29 g,96%) as colorless crystals.

mp 66-68° C. IR ν max^(KBr) (cm⁻¹): 3117, 1739, 1693, 1628, 1483, 1304,1219, 1153, 1028 ¹H-NMR (CDCl₃) δ (ppm) 1.24, 1.34 (3H, each t, J=7.0,7.2 Hz respectively) 4.15 (1.2H, s) 4.21, 4.28 (2H, each q, J=6.8, 7.2Hz respectively) 6.21 (0.4H, s) 7.41-7.49 (3H, m), 7.83 (0.4H, s)7.93-7.99 (2H, m), 8.19 (0.6H, s) 12.16 (0.4H, s)

2) ethyl3-oxo-3-(2-phenyl-1,3-thiazol-4-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate

To a solution of 3-(1,1,2,2-tetrafluoroethoxy)benzyl alcohol (5.53 ml,24.7 mmol) in ethyl acetate (50 ml) was added triethylamine (5.2 ml,37.05 mmol). Methanesulfonyl chloride (2.1 ml, 27.17 mmol) was addeddropwise under ice-cooling, and the mixture was stirred as it was for 30min. The precipitated crystals were filtered off, and the filtrate wasconcentrated to give mesylate, which was directly used in the nextreaction.

A solution of ethyl 3-oxo-3-(2-phenyl-1,3-thiazol-4-yl)propionate (6.80g, 24.7 mmol) in dimethoxyethane (50 ml) was ice-cooled. Sodium hydride(60%, 0.99 g, 24.7 mmol) was added, and the mixture was stirred underice-cooling for 30 min. A solution of the mesylate in dimethoxyethane(50 ml) was added thereto, and the mixture was stirred overnight at roomtemperature. After completion of the reaction, the reaction was quenchedwith 1N hydrochloric acid, and the mixture was diluted with ethylacetate, washed with water and saturated brine, dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=10:1, 5:1) to give ethyl3-oxo-3-(2-phenyl-1,3-thiazol-4-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate(8.65 g, 73%) as a pale-yellow oil.

IR ν max^(KBr) (cm⁻¹): 1736, 1691, 1612, 1587, 1487, 1467, 1444, 1197,1122 ¹H-NMR (CDCl₃) δ (ppm) 1.12 (3H, t, J=7.2 Hz), 3.37 (2H, m), 4.12(2H, q, J=7.0 Hz), 4.84 (1H, dd, J=7.0, 7.8 Hz), 5.87 (1H, dt, J=2.8,53.0 Hz), 7.02-7.06 (1H, m), 7.18-7.32 (3H, m), 7.44-7.51 (3H, m),7.94-7.98 (2H, m), 8.19 (1H, s).

3) ethyl3-hydroxy-3-(2-phenyl-1,3-thiazol-4-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate

To a suspension (50 ml) of zinc chloride (3.41 g, 25 mmol) in ether wasadded sodium borohydride (1.89 g, 50 mmol) at room temperature, and themixture was stirred as it was for 2 hrs. Insoluble material was filteredoff. To the filtrate was added a solution of ethyl3-oxo-3-(2-phenyl-1,3-thiazol-4-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate(6.01 g, 12.5 mmol) in ether (40 ml) under ice-cooling, and the mixturewas stirred as it was for 1 hr. The reaction was quenched with 1Nhydrochloric acid. The mixture was diluted with ethyl acetate, washedwith water and saturated brine, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=6:1,4:1) to give ethyl3-hydroxy-3-(2-phenyl-1,3-thiazol-4-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate(4.61 g, 76%) as a colorless transparent oil.

IR ν max^(KBr) (cm⁻¹): 1726, 1612, 1587, 1460, 1302, 1277, 1197, 1120¹H-NMR (CDCl₃) δ (ppm) 0.96-107 (3H, m), 2.93-3.15 (2H, m), 3.36-3.49(1H, m), 3.54 (0.74H, d, J=5.2 Hz), 3.69 (0.26H, d, J=9.4 Hz), 3.99,4.01 (2H, each q, J=6.8, 7.0 Hz), 4.94 (0.26H, dd, J=5.6, 9.6 Hz),5.18-5.23 (0.74H, m), 5.85, 5.89 (1H, each dt, J=3.0, 53.0 Hz),6.99-7.32 (5H, m), 7.39-7.47 (3H, m), 7.89-7.95 (2H, m).

(The syn:anti-ratio was determined to be 2.8:1 according to the integralratio of the peaks at 4.94 ppm and 5.18-5.23 ppm.)

4)3-hydroxy-3-(2-phenyl-1,3-thiazol-4-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionicacid

To a solution of ethyl3-hydroxy-3-(2-phenyl-1,3-thiazol-4-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionate(6.28 g, 13.0 mmol) in tetrahydrofuran-ethanol (20 ml—20 ml) was added2N sodium hydroxide (17 ml, 34 mmol) at room temperature, and themixture was stirred overnight at room temperature. After completion ofthe reaction, the organic solvent was evaporated under reduced pressureand diluted with water. The aqueous layer was washed with ether andacidified with 1N hydrochloric acid, and the mixture was extracted withethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate, filtered, and concentrated under reduced pressure to give3-hydroxy-3-(2-phenyl-1,3-thiazol-4-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionicacid (5.51 g, 93%) as a pale-yellow oil.

IR ν max^(KBr) (cm⁻¹): 250-3300, 1707, 1612, 1587, 1458, 1278, 1197,1120 ¹H-NMR (CDCl₃) δ (ppm) 2.85-3.14 (2H, m), 3.39-3.52 (1H, m), 4.93(0.33H, d, J=5.8 Hz), 5.24 (0.66H, d, J=4.4 Hz), 5.81, 5.85 (1H, dt,J=3.0, 53.0 Hz, J=3.0, 56.0 Hz respectively) 6.98-7.31 (5H, m),7.39-7.45 (3H, m), 7.82-7.89 (2H, m).

(The syn:anti-ratio was determined to be 2:1 according to the integralratio of the peaks at 4.93 ppm and 5.24 ppm.)

5)5-(2-phenyl-1,3-thiazol-4-yl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one

To a solution of3-hydroxy-3-(2-phenyl-1,3-thiazol-4-yl)-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propionicacid (5.23 g, 11.48 mmol) in tetrahydrofuran (120 ml) were addedtriethylamine (2.40 ml, 17.22 mmol) and diphenylphosphoryl azide (2.73ml, 12.63 mmol), and the mixture was heated under reflux for 5 hrs. Thesolvent was evaporated, and the residue was diluted with ethyl acetateand washed with water, saturated aqueous sodium hydrogen carbonate andsaturated brine. The organic layer was dried over anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane:ethylacetate=3:1, 1:1) to give5-(2-phenyl-1,3-thiazol-4-yl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one(4.57 g, 88%) as a pale-yellow oil.

IR ν max^(KBr) (cm⁻¹): 3260, 1761, 1612, 1587, 1462, 1302, 1277, 1197,1120 ¹H-NMR (CDCl₃) δ (ppm) 2.33 (0.66H, dd, J=11.0, 13.8 Hz), 2.71(0.66H, dd, J=4.0, 14.0 Hz), 3.01 (0.33H, dd, J=8.8, 13.8 Hz) 3.26(0.33H, dd, J=5.0, 13.4 Hz), 4.27-4.51 (1H, m), 5.20 (0.66H, m), 5.42(0.33H, d, J=5.5 Hz), 5.30-5.50 (0.33H, br) 5.61-5.65 (0.25H, m),5.87-5.91 (0.5H, m), 6.00 (0.66H, d, J=8.2 Hz), 6.13-6.16 (0.25H, m),6.95-7.19 (3H, m), 7.19-7.47 (5H, m) 7.90-7.95 (2H, m).

6) tert-butyl(4RS,5RS)-2-oxo-5-(2-phenyl-1,3-thiazol-4-yl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate

To a solution of5-(2-phenyl-1,3-thiazol-4-yl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one(4.43 g, 9.79 mmol) in acetonitrile (50 ml) were successively addeddi-tert-butyl-dicarbonate (2.58 g, 11.8 mmol) and4-(dimethylamino)pyridine (0.12 g, 0.98 mmol), and the mixture wasstirred overnight at room temperature. The solvent was evaporated underreduced pressure, and the residue was purified by flash columnchromatography (hexane:ethyl acetate:toluene=4:1:1) to give tert-butyl(4RS,5RS)-2-oxo-5-(2-phenyl-1,3-thiazol-4-yl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate(3.40 g, 63%) to give a pale-yellow oil.

Syn (4RS,5RS) form (more polar) IR ν max^(KBr) (cm⁻¹): 1824, 1724, 1612,1587, 1489, 1464, 1356, 1116 ¹H-NMR (CDCl₃) δ (ppm): 1.49 (9H, s) 2.78(1H, dd, J=8.2, 14.0 Hz), 2.94 (1H, dd, J=4.6, 13.8 Hz), 4.98-5.08 (1H,m), 5.79-5.83 (1H, m), 5.82 (1H, dt, J=3.0, 53.0 Hz), 6.69 (2H, d, J=7.4Hz), 6.81 (1H, d, J=8.0 Hz), 6.99-7.07 (1H, m), 7.15-7.29 (1H, m),7.34-7.43 (3H, m), 7.68-7.73 (2H, m). anti (4RS,5SR) form (less polar)IR ν max^(KBr) (cm⁻¹): 1871, 1724, 1612, 1587, 1489, 1464, 1356, 1116¹H-NMR (CDCl₃) δ (ppm): 1.59 (9H, s) 3.06 (1H, dd, J=8.8, 13.6 Hz), 3.44(1H, dd, J=4.2, 14.0 Hz), 4.73-4.81 (1H, m), 5.28 (1H, dd, J=1.2, 3.0Hz), 5.90 (1H, dt, J=2.8, 53.0 Hz) 7.18-7.25 (4H, m), 7.34-7.45 (4H, m),7.82-7.87 (2H, m).

7) tert-butyl(1RS,2RS)-2-hydroxy-2-(2-phenyl-1,3-thiazol-4-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate

To a solution of tert-butyl(4RS,5RS)-2-oxo-5-(2-phenyl-1,3-thiazol-4-yl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate(3.17 g, 5.74 mmol) in methanol (60 ml) was added 1N sodium hydroxide(6.9 ml, 6.9 mmol), and the mixture was stirred overnight at roomtemperature. The mixture was diluted with water and extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure. The residue was purified by recrystallization (hexane-ethylacetate) to give tert-butyl(1RS,2RS)-2-hydroxy-2-(2-phenyl-1,3-thiazol-4-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate(1.72 g, 57%) as colorless crystals.

mp 127-128° C. IR ν max^(KBr) (cm⁻¹): 3341, 1691, 1612, 1587, 1508,1558, 1367, 1278, 1195, 1167, 1122 ¹H-NMR (CD₃OD) δ (ppm): 1.39 (9H, s)2.80 (1H, dd, J=6.0, 14.1 Hz), 2.92 (1H, dd, J=8.7, 14.1 Hz), 3.96 (1H,d, J=6.0 Hz) 4.29-4.34 (1H, m), 4.97 (1H, s) 5.22 (1H, d, J=5.8 Hz) 5.88(1H, dt, J=2.7, 53.7 Hz), 7.07 (2H, s) 7.12 (1H, d, J=7.2 Hz), 7.24-7.30(2H, m), 7.44-7.46 (3H, m), 7.95-7.98 (2H, m).

Example 3624-fluoro-N-{(1RS,2RS)-2-hydroxy-2-(2-phenyl-1,3-thiazol-4-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-1-naphthamide

1)(1RS,2RS)-2-amino-1-(2-phenyl-1,3-thiazol-4-yl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-1-propanol

To a solution of tert-butyl(1RS,2RS)-2-hydroxy-2-(2-phenyl-1,3-thiazol-4-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate(1.67 g, 3.17 mmol) in chloroform (20 ml) was added trifluoroacetic acid(20 ml), and the mixture was stirred at room temperature for 1 hr. Themixture was concentrated under reduced pressure. To the residue wasadded water, and the mixture was basified with saturated aqueous sodiumhydrogen carbonate. The aqueous layer was extracted with ethyl acetate,dried over anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The residue was purified by recrystallization(hexane-ethyl acetate) to give(1RS,2RS)-2-amino-1-(2-phenyl-1,3-thiazol-4-yl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-1-propanol(1.17 g, 87%) as colorless crystals.

mp 128-130° C. IR ν max^(KBr) (cm⁻¹): 3300, 1676, 1462, 1199, 1126¹H-NMR (CDCl₃) δ (ppm): 2.76 (1H, dd, J=7.8, 14.1 Hz), 3.00 (1H, dd,J=6.3, 14.1 Hz), 3.77-3.83 (1H, m), 4.93 (1H, dd, J=0.9, 4.2 Hz), 6.27(1H, dt, J=3.0, 52.5 Hz), 7.07 (1H, d, J=8.1 Hz), 7.16-7.20 (2H, m),7.33 (1H, t, J=7.8 Hz), 7.46-7.49 (4H, m), 7.93-7.97 (2H, m).

2) 4-fluoro-N-{(1RS,2RS)2-hydroxy-2-(2-phenyl-1,3-thiazol-4-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-1-naphthamide

To a solution of(1RS,2RS)-2-amino-1-(2-phenyl-1,3-thiazol-4-yl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-1-propanol(311 mg, 0.73 mmol) in N,N-dimethylformamide (10 ml) were added4-fluoronaphthalene-1-carboxylic acid (133 mg, 0.70 mmol) and1-hydroxybenzotriazole monohydrate (112 mg, 0.73 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg,0.73 mmol) was finally added. The mixture was stirred at roomtemperature for 3 days. The mixture was diluted with ethyl acetate,washed with saturated aqueous sodium hydrogen carbonate solution, waterand saturated brine, dried over anhydrous magnesium sulfate, filteredand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate=5:1, 1:2) andrecrystallization (hexane-ethyl acetate) to give4-fluoro-N-{(1RS,2RS)-2-hydroxy-2-(2-phenyl-1,3-thiazol-4-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-1-naphthamide(217 mg, 52%) as colorless crystals.

mp 148-150° C. IR ν max^(KBr) (cm⁻¹): 3258, 1641, 1514, 1462, 1197, 1124Elemental analysis for C₃₁H₂₃N₂O₃SF₅ Calcd: C, 62.20; H, 3.87; N, 4.68.Found: C, 62.06; H, 3.78; N, 4.63. ¹H-NMR (CDCl₃) δ (ppm) 2.95 (1H, dd,J=6.0, 13.6 Hz), 3.13 (1H, dd, J=5.6, 14.0 Hz), 3.95 (1H, d, J=6.0 Hz),4.89-5.02 (1H, m) 5.08-512 (1H, m), 5.87 (1H, dt, J=2.8, 53.0 Hz),6.99-7.08 (4H, m), 7.21-7.59 (8H, m), 7.81-7.86 (2H, m), 8.09-8.15 (2H,m).

Example 363N-{(1RS,2RS)-2-hydroxy-2-(2-phenyl-1,3,-thiazol-4-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution of(1RS,2RS)-2-amino-1-(2-phenyl-1,3-thiazol-4-yl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-1-propanol(310 mg, 0.73 mmol) in acetonitrile (10 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (132 mg, 0.70mmol) and 1-hydroxybenzotriazole monohydrate (112 mg, 0.73 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg,0.73 mmol) was finally added. The mixture was stirred at roomtemperature for 3 days. The mixture was diluted with ethyl acetate,washed with saturated aqueous sodium hydrogen carbonate solution, waterand saturated brine, dried over anhydrous magnesium sulfate, filteredand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate=5:1, 2:1) andrecrystallization (hexane-ethyl acetate) to giveN-{(1RS,2RS)-2-hydroxy-2-(2-phenyl-1,3-thiazol-4-yl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(247 mg, 59%) as colorless crystals.

mp 137-138° C. Elemental analysis for C₃₂H₂₈ N₂O₃SF₄ Calcd: C, 64.42; H,4.73; N, 4.70. Found: C, 64.34; H, 4.64; N, 4.55. IR ν max^(KBr) (cm⁻¹):3265, 1641, 1512, 1304, 1195, 1122 ¹H-NMR (CDCl₃) δ (ppm) 1.96-2.05 (2H,m), 2.12-2.22 (2H, m), 2.64-2.70 (2H, m), 3.00 (1H, dd, J=6.2, 14.2 Hz),3.14 (1H, dd, J=8.6, 13.8 Hz), 4.34 (1H, d, J=5.8 Hz), 4.75-4.89 (1H,m), 5.08 (1H, dd, J=2.6, 5.4 Hz), 5.88 (1H, dt, J=3.0, 53.0 Hz) 5.94(1H, dt, J=5.6, 11.6 Hz), 6.36 (1H, d, J=11.8 Hz), 6.50 (1H, d, J=8.0Hz), 7.04-7.34 (8H, m), 7.42-7.47 (3H, m), 7.89-7.93 (2H, m).

Example 364N-[(1RS,2SR)-1-(4-tert-butylbenzyl)-2-(4-fluorophenyl)-2-hydroxyethyl]-5-fluoro-1-naphthamide

To a solution of(1RS,2RS)-2-amino-3-[4-(tert-butyl)benzyl]-1-(4-fluorophenyl)propan-1-ol(0.22 g, 0.70 mmol) in N,N-dimethylformamide (10 ml) were added5-fluoronaphthalene-1-carboxylic acid (122 mg, 0.64 mmol) and1-hydroxybenzotriazole monohydrate (108 mg, 0.70 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg,0.70 mmol) was finally added. The mixture was stirred overnight at roomtemperature. The mixture was diluted with ethyl acetate, washed withsaturated aqueous sodium hydrogen carbonate solution, water andsaturated brine, dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=2:1) andrecrystallization (hexane-ethyl acetate) to giveN-[(1RS,2SR)-1-(4-tert-butylbenzyl)-2-(4-fluorophenyl)-2-hydroxyethyl]-5-fluoro-1-naphthamide(153 mg, 50%) as colorless crystals.

mp 148-149° C. Elemental analysis for C₃₀H₂₉NO₂F₂ Calcd: C, 76.09; H,6.17; N, 2.96. Found: C, 76.02; H, 6.16; N, 2.78. IR ν max^(KBr) (cm⁻¹):3267, 1637, 1508, 1412, 1244, 1224 ¹H-NMR (CDCl₃) δ (ppm) 1.31 (9H, s)2.73 (1H, dd, J=10.8, 14.4 Hz), 3.03 (1H, dd, J=4.5, 14.4 Hz), 3.82 (1H,d, J=2.6 Hz) 4.77-4.84 (1H, m), 5.06-5.08 (1H, m), 5.84 (1H, d, J=5.6Hz) 7.04-7.17 (6H, m), 7.26-7.57 (6H, m), 7.59 (1H, d, J=5.6 Hz) 8.14(1H, d, J=5.4 Hz).

Example 365N-[(1RS,2SR)-1-(4-tert-butylbenzyl)-2-(4-fluorophenyl)-2-hydroxyethyl]-5-chloro-1-naphthamide

To a solution of(1RS,2RS)-2-amino-3-[4-(tert-butyl)benzyl]-1-(4-fluorophenyl)propan-1-ol(0.34 g, 1.1 mmol) in N,N-dimethylformamide (10 ml) were added5-chloronaphthalene-1-carboxylic acid (208 mg, 1.0 mmol) and1-hydroxybenzotriazole monohydrate (170 mg, 1.1 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (210 mg, 1.1mmol) was finally added. The mixture was stirred overnight at roomtemperature. The mixture was diluted with ethyl acetate, washed withsaturated aqueous sodium hydrogen carbonate solution, water andsaturated brine, dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=2:1) andrecrystallization (hexane-ethyl acetate) to giveN-[(1RS,2SR)-1-(4-tert-butylbenzyl)-2-(4-fluorophenyl)-2-hydroxyethyl]-5-chloro-1-naphthamide(265 mg, 57%) as colorless crystals.

Elemental analysis for C₃₀H₂₉NO₂CIF Calcd: C, 73.53; H, 5.97; N, 2.86.Found: C, 73.68; H, 5.93; N, 2.75. IR ν max^(KBr) (cm⁻¹): 3261, 1637,1508, 1222, 1157 ¹H-NMR (CDCl₃) δ (ppm) 1.31 (9H, s) 2.72 (1H, dd,J=10.6, 14.2 Hz), 3.03 (1H, dd, J=4.4, 14.4 Hz), 3.73 (1H, d, J=3.6 Hz)4.72-4.86 (1H, m), 5.03-5.07 (1H, m), 5.83 (1H, d, J=8.4 Hz) 7.01-7.13(5H, m), 7.15-7.47 (6H, m), 7.56 (1H, dd, J=1.0, 7.6 Hz), 7.70 (1H, d,J=8.8 Hz), 8.31 (1H, d, J=8.4 Hz).

Example 366N-[(1RS,2SR)-1-[3-(neopentyloxy)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide

1) methyl 3-(neopentyloxy)benzoate

To a solution of methyl 3-hydroxybenzoate (7.68 g, 50.5 mmol) inN,N-dimethylformamide (100 ml) were added potassium carbonate (13.96 g,101 mmol) and neopentyl iodide (10 g, 50.5 mmol), and the mixture wasstirred at 100° C. overnight. The mixture was diluted with ethylacetate, water and saturated brine, dried over anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane:ethylacetate=20:1, 10:1) to give methyl 3-(neopentyloxy)benzoate (4.69 g,42%) as a colorless transparent oil.

IR ν max^(KBr) (cm⁻¹): 1724, 1601, 1587, 1489, 1477, 1444, 1400, 1365,1292, 1278, 1224 ¹H-NMR (CDCl₃) δ (ppm) 1.04 (9H, s) 3.63 (2H, s) 3.91(3H, s) 7.10 (1H, ddd, J=0.8, 2.6, 8.2 Hz), 7.32 (1H, t, J=7.8 Hz)7.54-7.56 (1H, m), 7.60 (1H, dt, J=1.4, 7.8 Hz).

2) 3-(neopentyloxy)benzyl lcohol

To a solution of methyl 3-(neopentyloxy)benzoate (4.51 g, 20.3 mmol) intetrahydrofuran (100 ml) was added lithium aluminum hydride (1.93 g,50.75 mmol) by small portions under ice-cooling, and the mixture wasstirred at room temperature for 2 hrs. To the mixture were successivelyadded slowly water (2 ml), 15% aqueous sodium hydroxide solution (2 ml)and water (6 ml) under ice-cooling. The obtained solid was filtered withcelite, washed thoroughly with ethyl acetate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=5:1) to give 3-(neopentyloxy)benzylalcohol (3.81 g, 97%) as a colorless transparent oil.

IR ν max^(KBr) (cm⁻¹): 3231, 1601, 1585, 1489, 1477, 1448, 1400, 1363,1259, 1155 ¹H-NMR (CDCl₃) δ (ppm) 1.03 (9H, s) 1.81 (1H, br) 3.59 (2H,s) 4.65 (2H, s) 6.80-6.93 (3H, m), 7.25 (1H, t, J=7.6 Hz).

3) 6-ethyl 2-[3-(neopentyloxy)benzyl]-3-(3-chlorophenyl)-3-oxopropionate

To a solution of 3-(neopentyloxy)benzyl alcohol (3.76 g, 19.4 mmol) inethyl acetate (40 ml) was added triethylamine (4.06 ml, 29.1 mmol).Methanesulfonyl chloride (1.65 ml, 21.34 mmol) was added dropwise underice-cooling, and the mixture was stirred as it was for 45 min. Theprecipitated crystals were filtered off, and the filtrate wasconcentrated to give mesylate, which was directly used in the nextreaction.

A solution of ethyl 3-(3-chlorophenyl)-3-oxopropionate (4.40 g, 19.4mmol) in dimethoxyethane (40 ml) was ice-cooled, and sodium hydride(60%, 0.78 g, 19.4 mmol) was added, and the mixture was stirred underice-cooling for 30 min. A solution of the mesylate in dimethoxyethane(30 ml) was added thereto, and the mixture was stirred overnight at roomtemperature. After completion of the reaction, the reaction was quenchedwith 1N hydrochloric acid. The mixture was diluted with ethyl acetate,washed with water and saturated brine, dried over anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane:ethylacetate=15:1, 7:1) to give ethyl2-[3-(neopentyloxy)benzyl]-3-(3-chlorophenyl)-3-oxopropionate (7.11 g,91%) as a pale-yellow oil.

IR ν max^(KBr) (cm⁻¹): 1736, 1691, 1585, 1475, 1448, 1365, 1255, 1226,1159 ¹H-NMR (CDCl₃) δ (ppm) 1.01 (9H, s) 1.14 (3H, t, J=7.2 Hz) 3.28(2H, d, J=7.4 Hz), 3.52 (2H, s) 4.12 (2H, q, J=6.8 Hz) 4.55 (1H, t,J=7.4 Hz), 6.69-6.78 (3H, m), 7.11-7.18 (1H, m), 7.33-7.41 (1H, m),7.49-7.55 (1H, m), 7.82 (1H, dt, J=1.0, 7.6 Hz) 7.90-7.92 (1H, m).

4) ethyl(2RS,3RS)-2-[3-(neopentyloxy)benzyl]-3-(3-chlorophenyl)-3-hydroxypropionate

To a suspension (60 ml) of zinc chloride (4.75 g, 34.8 mmol) in etherwas added sodium borohydride (2.64 g, 69.6 mmol) at room temperature,and the mixture was stirred as it was for 2 hrs. Insoluble material wasfiltered off. To the filtrate was added a solution of ethyl2-[3-(neopentyloxy)benzyl]-3-(3-chlorophenyl)-3-oxopropionate (2.64 g,69.6 mmol) in ether (40 ml), and the mixture was stirred at roomtemperature for 1 hr. The reaction was quenched with 1N hydrochloricacid. The mixture was diluted with ethyl acetate, washed with water andsaturated brine, dried over anhydrous magnesium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=8:1, 3:1) to give ethyl(2RS,3RS)-2-[3-(neopentyloxy)benzyl]-3-(3-chlorophenyl)-3-hydroxypropionate(5.82 g, 81%) as a colorless transparent oil.

IR ν max^(KBr) (cm⁻¹): 3472, 1726, 1599, 1583, 1477, 1448, 1400, 1257,1159 ¹H-NMR (CDCl₃) δ (ppm) 0.98 (3H, t, J=7.4 Hz), 1.01 (9H, s)2.84-2.99 (3H, m), 3.10 (1H, d, J=2.4 Hz), 3.93 (2H, q, J=7.4 Hz), 5.01(1H, t, J=3.0 Hz), 6.61-6.72 (3H, m), 7.08-7.15 (1H, m), 7.25-7.28 (3H,m), 7.41 (1H, s).

5)(4RS,5SR)-4-[3-(neopentyloxy)benzyl]-5-(3-chlorophenyl)-1,3-oxazolidin-2-one

To a solution of ethyl(2RS,3RS)-2-[3-(neopentyloxy)benzyl]-3-(3-chlorophenyl)-3-hydroxypropionate(5.71 g, 14.1 mmol) in tetrahydrofuran-ethanol (15 ml—15 ml) was added2N sodium hydroxide (15 ml, 30 mmol) at room temperature, and themixture was stirred overnight at room temperature. After completion ofthe reaction, the organic solvent was evaporated under reduced pressure,and the aqueous layer was acidified with 1N hydrochloric acid andextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate and filtered, and the filtrate was concentrated underreduced pressure to give a colorless transparent oil.

To a solution of the oil obtained above in tetrahydrofuran (150 ml) wereadded triethylamine (2.95 ml, 21.15 mmol) and diphenylphosphoryl azide(3.35 ml, 15.51 mmol), and the mixture was heated under reflux for 4hrs. The solvent was evaporated. The mixture was diluted with ethylacetate, and washed with water, saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure. Recrystallization from hexane-ethyl acetate gave(4RS,5SR)-4-[3-(neopentyloxy)benzyl]-5-(3-chlorophenyl)-1,3-oxazolidin-2-one(4.15 g, 79%) as colorless crystals.

mp 141-142° C. IR ν max^(KBr) (cm⁻¹): 3248, 1763, 1601, 1583, 1477,1400, 1363 ¹H-NMR (CDCl₃) δ (ppm) 1.02 (9H, s) 2.15 (1H, dd, J=10.8,13.2 Hz), 2.29 (1H, dd; J=4.2, 14.1 Hz), 3.54 (2H, s) 4.21-4.28 (1H, m),4.99 (1H, s) 5.76 (1H, d, J=7.8 Hz), 6.57-6.62 (2H, m), 6.76 (1H, dd,J=2.1, 7.8 Hz), 7.16-7.21 (1H, m), 7.26-7.28 (1H, m), 7.34-7.39 (3H, m).

6)(1RS,2SR)-2-amino-3-[3-(neopentyloxy)phenyl]-1-(3-chlorophenyl)-1-propanol

To a solution of(4RS,5SR)-4-[3-(neopentyloxy)benzyl]-5-(3-chlorophenyl)-1,3-oxazolidin-2-one(4.0 g, 10.7 mmol) in ethanol (80 ml) was added 8N aqueous sodiumhydroxide solution (6.7 ml, 53.5 mmol), and the mixture was heated underreflux for 5 hrs. After completion of the reaction, the mixture wasdiluted with water and extracted with ethyl acetate. The organic layerswere combined, washed with saturated brine, dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by recrystallization (hexane-ethyl acetate) to give(1RS,2SR)-2-amino-3-[3-(neopentyloxy)phenyl]-1-(3-chlorophenyl)-1-propanol(2.95 g, 79%) as colorless crystals.

mp 115-116° C. IR ν max^(KBr) (cm⁻¹): 3300, 1599, 1583, 1477, 1448,1400, 1363, 1255, 1159, 1053 ¹H-NMR (CDCl₃) δ (ppm) 1.02 (9H, s) 2.29(1H, dd, J=10.4, 13.6 Hz), 2.72 (1H, dd, J=3.0, 13.6 Hz), 3.30 (1H, dt,J=3.8, 14.4 Hz), 3.55 (2H, s) 4.66 (1H, d, J=4.8 Hz), 6.67-6.77 (3H, m)7.14-7.30 (4H, m), 7.41 (1H, s).

7)N-[(1RS,2SR)-1-[3-(neopentyloxy)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide

To a solution of(1RS,2SR)-2-amino-3-[3-(neopentyloxy)phenyl]-1-(3-chlorophenyl)-1-propanol(0.30 g, 0.86 mmol) in N,N-dimethylformamide (5 ml) were added4-fluoronaphthalene-1-carboxylic acid (0.17 g, 0.90 mmol) and1-hydroxybenzotriazole monohydrate (0.138 g, 0.90 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.173 g,0.90 mmol) was finally added. The mixture was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate,washed with saturated aqueous sodium hydrogen carbonate solution, waterand saturated brine, dried over anhydrous magnesium sulfate, filteredand concentrated under reduced pressure. The residue was purified byrecrystallization (hexane-ethyl acetate) to giveN-[(1RS,2SR)-1-[3-(neopentyloxy)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide(0.354 g, 79%) as colorless crystals.

mp 165-166° C. IR ν max^(KBr) (cm⁻¹): 3263, 1639, 1599, 1583, 1518,1477, 1448, 1400, 1259 ¹H-NMR (CDCl₃) δ (ppm) 0.99 (9H, s) 2.73 (1H, dd,J=11.0, 14.4 Hz) 3.01 (1H, dd, J=4.0, 14.4 Hz), 3.52 (2H, dd, J=8.6,11.4 Hz), 4.17 (1H, br) 4.70-4.81 (1H, m), 5.09 (1H, s) 5.87 (1H, d,J=7.2 Hz), 6.74-6.83 (3H, m), 7.00 (1H, dd, J=7.6, 9.8 Hz) 7.18-7.36(5H, m), 7.41-7.57 (3H, m), 7.80 (1H, d, J=7.6 Hz) 8.07 (1H, d, J=7.6Hz).

Example 367N-[(1RS,2SR)-1-[3-(neopentyloxy)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-5-chloro-1-naphthamide

To a solution of(1RS,2SR)-2-amino-3-[3-(neopentyloxy)phenyl]-1-(3-chlorophenyl)-1-propanol(0.30 g, 0.86 mmol) in N,N-dimethylformamide (5 ml) were added5-chloronaphthalene-1-carboxylic acid (0.186 g, 0.90 mmol) and1-hydroxybenzotriazole monohydrate (0.138 g, 0.90 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.173 g,0.90 mmol) was finally added. The mixture was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate,washed with saturated aqueous sodium hydrogen carbonate solution, waterand saturated brine, dried over anhydrous magnesium sulfate, filtered,and concentrated under reduced pressure. The residue was purified byrecrystallization (hexane-ethyl acetate) to giveN-[(1RS,2SR)-1-[3-(neopentyloxy)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-5-chloro-1-naphthamide(0.350 g, 76%) as colorless crystals.

mp 142-143° C. IR ν max^(KBr) (cm⁻¹): 3252, 1637, 1518, 1477, 1448,1398, 1363, 1255, 1159, 1059, 1022 ¹H-NMR (CDCl₃) δ (ppm) 0.99 (9H, s)2.71 (1H, dd, J=11.0, 14.4 Hz), 2.98 (1H, dd, J=4.2, 14.4 Hz), 3.51 (2H,dd, J=8.8, 11.6 Hz), 4.05 (1H, br) 4.70-4.79 (1H, m), 5.04 (1H, d, J=3.4Hz) 5.97 (1H, d, J=7.6 Hz), 6.72-6.81 (3H, m), 7.16-7.62 (10H, m) 8.28(1H, d, J=8.4 Hz).

Example 368N-[(1RS,2SR)-1-[3-(neopentyloxy)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-3-[3-(neopentyloxy)phenyl]-1-(3-chlorophenyl)-1-propanol(0.40 g, 0.86 mmol) in N,N-dimethylformamide (5 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (0.17 g, 0.90mmol) and 1-hydroxybenzotriazole monohydrate (0.138 g, 0.90 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.173 g,0.90 mmol) was finally added. The mixture was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate,washed with saturated aqueous sodium hydrogen carbonate solution, waterand saturated brine, dried over anhydrous magnesium sulfate, filtered,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate=1:1, 0:1), andrecrystallization (hexane-ethyl acetate) to giveN-[(1RS,2SR)-1-[3-(neopentyloxy)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.174 g, 39%) as colorless crystals.

mp 128-129° C. IR ν max^(KBr) (cm⁻¹): 3265, 1633, 1599, 1585, 1514,1477, 1450, 1363, 1255, 1159 ¹H-NMR (CDCl₃) δ (ppm) 1.01 (9H, s)1.99-2.01 (1H, m), 2.14-2.20 (1H, m), 2.63-2.73 (3H, m), 2.94 (1H, dd,J=3.8, 13.6 Hz), 3.54 (2H, s) 4.33 (1H, d, J=4.4 Hz), 4.65 (1H, m), 5.03(1H, br) 5.71 (1H, d, J=6.6 Hz), 5.90-6.01 (1H, m), 6.26 (1H, d, J=11.6Hz), 6.71-6.78 (3H, m), 7.02-7.30 (7H, m).

Example 369N-[(1RS,2SR)-1-[3-(tert-butyl)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide

1) 3-tert-butylphenyl trifluoromethanesulfonate

To a solution of 3-tert-butylphenol (15 g, 100 mmol) in dichloromethane(300 ml) were added N-ethyldiisopropylamine (17.5 ml, 100 mmol) andN-phenyltrifluoromethanesulfonimide (44.7 g, 125 mmol), and the mixturewas stirred overnight at room temperature. Dichloromethane wasevaporated under reduced pressure. The mixture was diluted with ethylacetate, washed with water and saturated brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=30:1) to give 3-tert-butylphenyltrifluoromethanesulfonate (7.17 g, 25%) as a colorless transparent oil.

IR ν max^(KBr) (cm⁻¹): 1612, 1577, 1489, 1423, 1246, 1215, 1145, 925¹H-NMR (CDCl₃) δ (ppm) 1.33 (9H, s) 7.06-7.10 (1H, m), 7.24-7.25 (1H,m), 7.33-7.42 (2H, m).

2) 3-tert-butylbenzylbenzonitrile

To a solution of 3-tert-butylphenyl trifluoromethanesulfonate (6.17 g,21.9 mmol) in acetonitrile (80 ml) were added sodium cyanide (2.15 g,43.8 mmol) and copper iodide (0.42 g, 2.19 mmol). To the mixture wasadded tetrakis(triphenylphosphine)palladium (1.27 g, 1.10 mmol) undernitrogen stream and the mixture was heated under reflux for 5 hrs. Themixture was diluted with ethyl acetate, and insoluble material wasfiltered off with celite. The filtrate was washed with water andsaturated brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ether=1:0, 20:1) to give3-tert-butylbenzylbenzonitrile (4.13 g) as a colorless transparent oil.The compound included impurities, but was directly used in the nextreaction.

IR ν max^(KBr) (cm⁻¹): 2229, 1599, 1579, 1485, 1417, 1365, 1273, 1113¹H-NMR (CDCl₃) δ (ppm) 1.32 (9H, s) 7.33-7.35 (2H, m), 7.39-7.50 (1H,m), 7.60-7.66 (1H, m).

3) 3-tert-butylbenzoic acid

To a suspension of 3-tert-butylbenzylbenzonitrile (4.13 g, 21.9 mmol) inwater (80 ml) was added sodium hydroxide (2.19 g, 54.8 mmol) and themixture was heated under reflux overnight. After completion of thereaction, the mixture was diluted with water, and the aqueous layer waswashed with ether. The aqueous layer was then acidified with 6Nhydrochloric acid, and extracted with ethyl acetate. The combinedorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated under reduced pressure togive 3-tert-butylbenzoic acid (3.23 g, 83% in 2 steps) as colorlesscrystals.

mp 96-97° C. IR ν max^(KBr) (cm⁻¹): 2500-3300, 1693, 1604, 1585, 1440,1412, 1286, 1259 ¹H-NMR (CDCl₃) δ (ppm): 1.36 (9H, s) 7.41 (1H, t, J=7.5Hz) 7.65 (1H, ddd, J=1.5, 2.1, 7.8 Hz), 7.94 (1H, dt, J=1.5, 7.8 Hz),8.16 (1H, t, J=1.8 Hz).

4) 3-tert-butylbenzyl Alcohol

To a suspension (40 ml) of lithium aluminum hydride (1.38 g, 36.2 mmol)in ether was added dropwise a solution of 3-tert-butylbenzoic acid (3.13g, 17.6 mmol) in ether (40 ml) under ice-cooling, and the mixture wasstirred at room temperature for 2 hrs. After completion of the reaction,water (1.38 ml), 15% aqueous sodium hydroxide solution (1.38 ml) andwater (4.2 ml) were successively added dropwise slowly underice-cooling. The obtained solid was filtered with celite, and washedwith ethyl acetate. The filtrate was concentrated, and the residue waspurified by silica gel column chromatography (hexane:ethyl acetate=8:1,4:1) to give 3-tert-butylbenzyl alcohol (2.59 g, 90%) as a colorlesstransparent oil.

IR ν max^(KBr) (cm⁻¹): 3277, 1606, 1489, 1363, 1275, 1203, 1016 ¹H-NMR(CDCl₃) δ (ppm) 1.32 (9H, s) 1.85 (1H, s) 4.66 (2H, s) 7.14-7.19 (1H,m), 7.29-7.38 (3H, m).

5) ethyl 2-[3-(tert-butyl)benzyl]-3-(3-chlorophenyl)-3-oxopropionate

To a solution of 3-tert-butylbenzyl alcohol (2.50 g, 15.2 mmol) in ethylacetate (30 ml) was added triethylamine (3.18 ml, 22.8 mmol).Methanesulfonyl chloride (1.29 ml, 16.72 mmol) was added dropwise underice-cooling, and the mixture was stirred as it was for 1 hr. Theprecipitated crystals were filtered off, and the filtrate wasconcentrated to give mesylate, which was directly used in the nextreaction.

A solution of ethyl 3-(3-chlorophenyl)-3-oxopropionate (3.45 g, 15.2mmol) in dimethoxyethane (30 ml) was ice-cooled, and sodium hydride(60%, 0.61 g, 15.2 mmol) was added. The mixture was stirred for 30 minunder ice-cooling. A solution of the mesylate in dimethoxyethane (25 ml)was added, and the mixture was stirred overnight at room temperature.After completion of the reaction, the reaction was quenched with 1Nhydrochloric acid. The mixture was diluted with ethyl acetate, washedwith water and saturated brine, dried over anhydrous magnesium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane-ethyl acetate=10:1,8:1) to give ethyl2-[3-(tert-butyl)benzyl]-3-(3-chlorophenyl)-3-oxopropionate (5.01 g,88%) as a pale-yellow oil.

IR ν max^(KBr) (cm⁻¹): 1739, 1691, 1572, 1475, 1423, 1365, 1228 ⁻¹H-NMR(CDCl₃) δ (ppm) 1.13 (3H, t, J=7.0 Hz), 1.25 (9H, s) 3.32 (2H, dd,J=2.2, 7.8 Hz), 4.12 (2H, dq, J=1.8, 7.4 Hz) 4.55 (1H, t, J=7.4 Hz),6.98-7.03 (1H, m), 7.18-7.21 (3H, m), 7.29-7.39 (1H, m), 7.48-7.53 (1H,m), 7.77 (1H, dt, J=1.6, 7.8 Hz) 7.85-7.87 (1H, m).

6) ethyl(2RS,3RS)-2-[3-(tert-butyl)benzyl]-3-(3-chlorophenyl)-3-hydroxypropionate

To a suspension (50 ml) of zinc chloride (3.60 g, 26.4 mmol) in etherwas added sodium borohydride (2.0 g, 52.8 mmol) at room temperature, andthe mixture was stirred as it was for 2 hrs. Insoluble material wasfiltered off. To the filtrate was added a solution of ethyl2-[3-(tert-butyl)benzyl]-3-(3-chlorophenyl)-3-oxopropionate (4.91 g,13.2 mmol) in ether (40 ml), and the mixture was stirred at roomtemperature for 1 hr. The reaction was quenched with 1N hydrochloricacid. The mixture was diluted with ethyl acetate, washed with water andsaturated brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=10:1, 3:1) to give ethyl(2RS,3RS)-2-[3-(tert-butyl)benzyl]-3-(3-chlorophenyl)-3-hydroxypropionate(4.16 g, 82%) as a colorless transparent oil.

IR ν max^(KBr) (cm⁻¹): 3456, 1728, 1599, 1477, 1373, 1346, 1180, 1032¹H-NMR (CDCl₃) δ (ppm) 0.92 (3H, t, J=7.0 Hz), 1.27 (9H, s) 2.88-3.02(3H, m), 3.14 (1H, d, J=3.0 Hz), 3.88 (2H, q, J=7.4 Hz), 4.99-5.01 (1H,m), 6.86-6.91 (1H, m), 7.07 (1H, s) 7.15-7.18 (2H, m), 7.25-7.27 (3H,m), 7.41 (1H, s).

7)(4RS,5SR)-4-[3-(tert-butyl)benzyl]-5-(3-chlorophenyl)-1,3-oxazolidin-2-one

To a solution of ethyl(2RS,3RS)-2-[3-(tert-butyl)benzyl]-3-(3-chlorophenyl)-3-hydroxypropionate(4.05 g, 10.8 mmol) in tetrahydrofuran-ethanol (10 ml-10 ml) was added2N sodium hydroxide (11 ml, 22 mmol) at room temperature, and themixture was stirred overnight at room temperature. After completion ofthe reaction, the organic solvent was evaporated under reduced pressure,and the aqueous layer was acidified with 1N hydrochloric acid andextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate, filtered, and concentrated under reduced pressure togive a colorless transparent oil.

To a solution of the oil obtained above in tetrahydrofuran (100 ml) wereadded triethylamine (2.26 ml, 16.2 mmol) and diphenylphosphoryl azide(2.56 ml, 11.88 mmol), and the mixture was heated under reflux for 4hrs. The solvent was evaporated, and the residue was diluted with ethylacetate, washed with water, saturated aqueous sodium hydrogen carbonateand saturated brine. The organic layer was dried over anhydrousmagnesium sulfate, filtered, and concentrated under reduced pressure andrecrystallized from hexane-ethyl acetate to give(4RS,5SR)-4-[3-(tert-butyl)benzyl]-5-(3-chlorophenyl)-1,3-oxazolidin-2-one(2.47 g, 60%) as colorless crystals.

mp 136-137° C. IR ν max^(KBr) (cm⁻¹): 3263, 1763, 1601, 1477, 1433,1363, 1234 ¹H-NMR (CDCl₃) δ (ppm) 1.28 (9H, s) 2.20 (1H, dd, J=11.1,13.8 Hz), 2.32 (1H, dd, J=3.9, 13.8 Hz), 4.23-4.30 (1H, m), 4.99 (1H, s)5.77 (1H, d, J=8.1 Hz), 6.85 (1H, d, J=7.2 Hz) 7.01 (1H, s) 7.19-7.31(3H, m), 7.34-7.40 (3H, m).

8)(1RS,2SR)-2-amino-3-[3-(tert-butyl)phenyl]-1-(3-chlorophenyl)-1-propanol

To a solution of(4RS,5SR)-4-[3-(tert-butyl)benzyl]-5-(3-chlorophenyl)-1,3-oxazolidin-2-one(2.36 g, 6.86 mmol) in ethanol (60 ml) was added 8N aqueous sodiumhydroxide (4.3 ml, 34.3 mmol), and the mixture was heated under refluxfor 5 hrs. After the completion of the reaction, ethanol was evaporatedunder reduced pressure. The residue was diluted with water and extractedwith ethyl acetate. The organic layers were combined, washed withsaturated brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified byrecrystallization (hexane-ethyl acetate) to give(1RS,2SR)-2-amino-3-[3-(tert-butyl)phenyl]-1-(3-chlorophenyl)-1-propanol(1.21 g, 55%) as colorless crystals.

mp 102-103° C. IR ν max^(KBr) (cm⁻¹): 3063, 1597, 1576, 1476, 1429,1363, 1199 ¹H-NMR (CDCl₃) δ (ppm) 1.30 (9H, s) 2.32 (1H, dd, J=10.4,13.6 Hz), 2.75 (1H, dd, J=3.2, 13.8 Hz), 3.31 (1H, dt, J=4.0, 9.6 Hz),4.68 (1H, d, J=4.8 Hz), 6.94-6.96 (1H, m), 7.13 (1H, s) 7.21-7.31 (5H,m), 7.42 (1H, s)

9)N-[(1RS,2SR)-1-[3-(tert-butyl)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide

To a solution of(1RS,2SR)-2-amino-3-[3-(tert-butyl)phenyl]-1-(3-chlorophenyl)-1-propanol(0.30 g, 0.944 mmol) in N,N-dimethylformamide (5 ml) were added4-fluoronaphthalene-1-carboxylic acid (0.189 g, 0.99 mmol) and1-hydroxybenzotriazole monohydrate (0.152 g, 0.99 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.190 g,0.99 mmol) was finally added. The mixture was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate,washed with saturated aqueous sodium hydrogen carbonate solution, waterand saturated brine, dried over anhydrous magnesium sulfate, filteredand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate=1:1, 0:1) andrecrystallization (hexane-ethyl acetate) to giveN-[(1RS,2SR)-1-[3-(tert-butyl)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide(0.245 g, 53%) as colorless crystals.

mp 76-78° C. IR ν max^(KBr) (cm⁻¹): 3312, 1639, 1599, 1516, 1425, 1261,1236, 1201, 1051 ¹H-NMR (CDCl₃) δ (ppm) 0.99 (9H, s) 2.73 (1H, dd,J=11.0, 14.4 Hz), 3.01 (1H, dd, J=4.0, 14.4 Hz), 3.52 (2H, dd, J=8.6,11.4 Hz), 4.17 (1H, br) 4.70-4.81 (1H, m), 5.09 (1H, s) 5.87 (1H, d,J=7.2 Hz), 6.74-6.83 (3H, m), 7.00 (1H, dd, J=7.6, 9.8 Hz) 7.18-7.36(5H, m), 7.41-7.57 (3H, m), 7.80 (1H, d, J=7.6 Hz) 8.07 (1H, d, J=7.6Hz).

Example 370N-[(1RS,2SR)-1-[3-(tert-butyl)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution of(1RS,2SR)-2-amino-3-[3(tert-butyl)phenyly]-(3-chlorophenyl)-1-propanol(0.30 g, 0.944 mmol) in N,N-dimethylformamide (5 ml) were added6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (0.187 g, 0.99mmol) and 1-hydroxybenzotriazole monohydrate (0.152 g, 0.99 mmol), and1-ethyl-3-(3-dimethyla1ninopropyl)carbodiimide hydrochloride (0.190 g,0.99 mmol) was finally added. The mixture was stirred at roomtemperature overnight, The mixture was diluted with ethyl acetate,washed with saturated aqueous sodium hydrogen carbonate solution, waterand saturated brine, dried over anhydrous magnesium sulfate, filtered,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate=1:1, 0:1) andrecrystallization (hexane-ethyl acetate) to giveN-[(1RS,2SR)-1-[3-(tert-butyl)benzyl]-2(3-chlorophenyl)2-hydroxyethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.230 g, 50%) as colorless crystals.

mp 104-105° C. IR ν max^(KBr) (cm⁻¹): 3300, 1635, 1514, 1425, 1363,1298, 1273, 1197, 1103, 1076 ¹H-NMR (CDCl₃) δ (ppm) 1.27 (9H, s)1.95-2.01 (2H, m), 2.14-2.20 (2H, m), 2.63-2.75 (3H, m), 297 (1H, dd,J=4.0, 14.2 Hz), 4.36 (1H, s) 4.67-4.69 (1H, m), 5.02 (1H, s) 5.69 (1H,d, J=7.4 Hz) 5.87-5.98 (1H, m), 6.26 (1H, d, J=12.0 Hz), 6.86-7.30 (10H,m) 7.47 (1H, s).

Example 371N-[(1RS,2SR)-1-[3-(tert-butyl)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-5-chloro-1-naphthamide

To a solution of(1RS,2SR)-2-amino-3-[3-(tert-butyl)phenyl]-1-(3-chlorophenyl)-1-propanol(0.313 g, 0.985 mmol) in N,N-dimethylformamide (5 ml) were added5-chloronaphthalene-1-carboxylic acid (0.214 g, 1.04 mmol) and1-hydroxybenzotriazole monohydrate (0.160 g, 1.04 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g,1.04 mmol) was finally added. The mixture was stirred overnight at roomtemperature. The mixture was diluted with ethyl acetate, washed withsaturated aqueous sodium hydrogen carbonate solution, water andsaturated brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified byrecrystallization (hexane-ethyl acetate) to giveN-[(1RS,2SR)-1-[3-(tert-butyl)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-5-chloro-1-naphthamide(0.307 g, 62%) as colorless crystals.

mp 91-93° C. IR ν max^(KBr) (cm⁻¹): 3267, 1631, 1572, 1518, 1203, 1037¹H-NMR (CDCl₃) δ (ppm) 1.25 (9H, s) 2.74 (1H, dd, J=11.0, 14.4 Hz), 3.05(1H, dd, J=4.0, 14.2 Hz), 4.02 (1H, d, J=4.4 Hz) 4.77-4.86 (1H, m),5.05-5.09 (1H, m), 5.87 (1H, d, J=7.8 Hz) 7.01 (1H, d, J=7.4 Hz),7.12-7.66 (12H, m), 8.29 (1H, d, J=8.8 Hz).

Example 372 tert-butyl(1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]ethylcarbamate

1) 2,2,3,3,3-pentafluoro-1-(4-methylphenyl)propan-1-ol

In a three neck flask purged with nitrogen were charged magnesium (12.2g, 502 mmol) and ether (100 ml). A solution of 4-bromotoluene (56.1 ml,456 mmol) in ether (200 ml) was added dropwise, and the mixture washeated under reflux for 1.5 hrs. The reaction vessel was cooled in a dryice-acetone bath. A solution of pentafluoropropionic acid (25 g, 152mmol) in ether (100 ml) was added dropwise, and the temperature wasslowly raised to room temperature. The mixture was heated under refluxfor 3 hrs, and stirred overnight at room temperature. The reactionmixture was ice-cooled, and quenched with 3N hydrochloric acid. Themixture was diluted with ethyl acetate, and the organic layer wasseparated and washed with saturated aqueous sodium hydrogen carbonateand saturated brine, dried over anhydrous magnesium sulfate, filteredand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate=1:0, 30:1) togive a colorless transparent oil. This was dissolved in methanol, andsodium borohydride was added under ice-cooling. The temperature wasraised to, room temperature, and the mixture was stirred for 1 hr. Aftercompletion of the reaction, the reaction was quenched with 6Nhydrochloric acid, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=10:1, 5:1) to give2,2,3,3,3-pentafluoro-1-(4-methylphenyl)propan-1-ol (20.28 g, 56%) as acolorless transparent oil.

IR ν max^(KBr) (cm⁻¹): 3400, 1616, 1518, 1363, 1331, 1213, 1184, 1132¹H-NMR (CDCl₃) δ (ppm) 2.37 (3H, s) 2.50 (1H, d, J=4.8 Hz) 4.98-5.13(1H, m), 7.21 (2H, d, J=8.4 Hz), 7.33 (2H, d, J=8.0 Hz).

2) O-phenylO-[2,2,3,3,3-pentafluoro-1-(4-methylphenyl)propyl]thiocarbonate

To a solution of 2,2,3,3,3-pentafluoro-1-(4-methylphenyl)propan-1-ol(15.93 g, 66.3 mmol) in ethyl acetate (200 ml) was added triethylamine(13.9 ml, 99.45 mmol), and chlorophenyl thionoformate (10.1 ml, 72.8mmol) was added under ice-cooling, and the mixture was stirred underice-cooling for 2 hrs. The precipitated solid was filtered off, and thefiltrated was washed with ethyl acetate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=30:1) to give O-phenylO-[2,2,3,3,3-pentafluoro-1-(4-methylphenyl)propyl]thiocarbonate (22.82g, 91%) as a colorless transparent oil.

IR ν max^(KBr) (cm⁻¹): 1616, 1591, 1518, 1491, 1290, 1192, 1143 ¹H-NMR(CDCl₃) δ (ppm) 2.39 (3H, s) 6.67 (1H, dd, J=7.5, 16.5 Hz) 7.05 (2H, d,J=8.1 Hz), 7.24-7.31 (3H, m), 7.37-7.42 (4H, m).

3) 4-(2,2,3,3,3-pentafluoropropyl)toluene

To a solution of O-phenylO-[2,2,3,3,3-pentafluoro-1-(4-methylphenyl)propyl]thiocarbonate (16.55g, 44.0 mmol) in benzene (100 ml) were added 2,2′-azobisisobutyronitrile(1.45 g, 8.8 minol) and tri-n-butyltin hydride (17.8 ml, 66.0 mmol), andthe mixture was stirred at 80° C. for 5 hrs. After completion of thereaction, benzene was evaporated under reduced pressure, and the residuewas purified by silica gel column chromatography (hexane) to give4-(2,2,3,3,3-pentafluoropropyl)toluene (11.13 g) as a colorlesstransparent oil. This contained some impurities, which were assumed tobe tin compounds, but was directly used in the next reaction.

IR ν max^(KBr) (cm⁻¹): 1518, 1464, 1377, 1315, 1203, 1118, 1080, 1030¹H-NMR (CDCl₃) δ (ppm) 2.34 (3H, s) 3.26 (2H, t, J=18.8 Hz) 7.16 (4H,s).

4) 1-(bromomethyl)-4-(2,2,3,3,3-pentafluoropropyl)benzene

To a solution of 4-(2,2,3,3,3-pentafluoropropyl)toluene (9.97 g, 39.4mmol) in carbon tetrachloride (300 ml) were added2,2′-azobisisobutyronitrile (0.33 g, 197 mmol) and N-bromosuccinimide(8.50 g, 47.3 mmol) and the mixture was heated under reflux overnight.After cooling to room temperature, insoluble material was filtered off,and the filtrated was concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (hexane:ethylacetate=1:0, 50:1, 20:1) to give1-(bromomethyl)-4-(2,2,3,3,3-pentafluoropropyl)benzene (3.66 g, 31%(yield by two steps)) as colorless crystals.

mp 62-63° C. IR ν max^(KBr) (cm⁻¹): 1518, 1437, 1323, 1190, 1101, 1070,1045 ¹H-NMR (CDCl₃) δ (ppm) 3.31 (2H, t, J=17.8 Hz), 7.27 (2H, d, J=8.0Hz), 7.40 (2H, d, J=8.4 Hz).

5) ethyl3-(3-chlorophenyl)-3-oxo-2-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]propionate

A solution of ethyl 3-(3-chlorophenyl)-3-oxopropionate (2.74 g, 12.08mmol) in dimethoxyethane (30 ml) was ice-cooled, and sodium hydride(60%, 0.49 g, 12.08 mmol) was added, and the mixture was stirred underice-cooling for 30 min. A solution of1-(bromomethyl)-4-(2,2,3,3,3-pentafluoropropyl)benzene (3.66 g, 12.08mmol) in dimethoxyethane (15 ml) was added, and the mixture was stirredovernight at room temperature. After completion of the reaction, thereaction was quenched with 0.5N hydrochloric acid. The mixture wasdiluted with ethyl acetate, washed with water and saturated brine, driedover anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=15:1, 10:1) to give ethyl3-(3-chlorophenyl)-3-oxo-2-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]propionate(4.64 g, 86%) as colorless crystals.

mp 81-82° C. IR ν max^(KBr) (cm⁻¹): 1738, 1693, 1572, 1425, 1317, 1195,1028 ¹H-NMR (CDCl₃) δ (ppm) 1.11 (3H, t, J=7.2 Hz), 3.25 (2H, t, J=18.3Hz), 3.32 (2H, d, J=7.2 Hz), 4.05-4.14 (2H, m), 4.54 (1H, t, J=7.5 Hz),7.16-7.23 (4H, m), 7.37 (1H, t, J=8.1 Hz) 7.51-7.54 (1H, m), 7.77-7.81(1H, m), 7.90-7.92 (1H, m).

6) ethyl(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]propionate

To a suspension (30 ml) of zinc chloride (2.70 g, 19.84 mmol) in etherwas added sodium borohydride (1.50 g, 39.68 mmol) at room temperatureand the mixture was stirred as it was for 2 hrs. Insoluble material wasfiltered off. To the filtrate was added a solution of ethyl3-(3-chlorophenyl)-3-oxo-2-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]propionate(4.45 g, 9.92 mmol) in ether (20 ml), and the mixture was stirred atroom temperature for 1 hr. The reaction was quenched with 1Nhydrochloric acid. The mixture was diluted with ethyl acetate, washedwith water and saturated brine, dried over anhydrous magnesium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=10:1,5:1) to give ethyl(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]propionate(3.95 g, 89%) as a colorless transparent oil.

IR ν max^(KBr) (cm⁻¹): 3450, 1709, 1576, 1518, 1435, 1315, 1195, 1113,1030 ¹H-NMR (CDCl₃) δ (ppm) 0.91 (3H, t, J=7.0 Hz), 2.87-3.02 (3H, m)3.18 (1H, d, J=2.6 Hz), 3.25 (2H, t, J=18.2 Hz), 3.88 (2H, q, J=6.8 Hz),5.02 (1H, d, J=1.8 Hz), 7.04-7.17 (4H, m), 7.26-7.28 (3H, m), 7.41-7.42(1H, m).

7)(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]propionicacid

To a solution of ethyl(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]propionate(3.84 g, 8.52 mmol) in tetrahydrofuran-ethanol (20 ml—20 ml) was added1N sodium hydroxide (17 ml, 17 mmol) at room temperature, and themixture was stirred overnight at room temperature. After completion ofthe reaction, the organic solvent was evaporated under reduced pressure,and the aqueous layer was acidified with 1N hydrochloric acid andextracted with ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was recrystallized from hexane-ethyl acetate to give(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]propionicacid (2.85 g, 79%) as colorless crystals.

mp 150-151° C. IR ν max^(KBr) (cm⁻¹): 2500-3300, 1693, 1433, 1315, 1238,1194, 1103, 1078, 1030 ¹H-NMR (CDCl₃) δ (ppm) 2.87-3.05 (3H, m), 3.24(2H, t, J=18.4 Hz) 5.09 (1H, d, J=4.0 Hz), 7.05 (2H, d, J=8.0 Hz), 7.14(2H, d, J=8.4 Hz), 7.24-7.29 (3H, m), 7.41 (1H, s).

8)(4RS,5SR)-5-(3-chlorophenyl)-4-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]propionicacid (2.75 g, 6.50 mmol) in tetrahydrofuran (70 ml) were addedtriethylamine (1.36 ml, 9.75 mmol) and diphenylphosphoryl azide (1.54ml, 7.15 mmol), and the mixture was heated under reflux for 4 hrs. Thesolvent was evaporated and the residue was diluted with ethyl acetate,washed with water, saturated. aqueous sodium hydrogen carbonate andsaturated brine. The organic layer was dried over anhydrous magnesiumsulfate, filtered, and concentrated under reduced pressure. The residueas recrystallized from hexane-ethyl acetate to give(4RS,5SR)-5-(3-chlorophenyl)-4-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]-1,3-oxazolidin-2-one(2.54 g, 93%) as colorless crystals.

mp 137-138° C. IR ν max^(KBr) (cm⁻¹): 3234, 1761, 1435, 1317, 1194,1030, 912 ¹H-NMR (CDCl₃) δ (ppm) 2.17-2.36 (2H, m), 3.28 (2H, t, J=18.6Hz) 4.19-4.30 (1H, m), 4.95 (1H, s) 5.77 (1H, d, J=8.2 Hz) 7.03 (2H, d,J=7.6 Hz), 7.27-7.38 (3H, m).

9) tert-butyl(4RS,5SR)-5-(3-chlorophenyl)-2-oxo-4-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]-1,3-oxazolidine-3-carboxylate

To a solution of(4RS,5SR)-5-(3-chlorophenyl)-4-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]-1,3-oxazolidin-2-one(2.43 g, 5.79 mmol) in acetonitrile (40 ml) were successively addeddi-tert-butyl dicarbonate (1.52 g, 6.95 mmol) and4-(dimethylamino)pyridine (71 mg, 0.579 mmol), and the mixture wasstirred overnight at room temperature. The solvent was evaporated underreduced pressure, and the residue was recrystallized from hexane-ethylacetate to give tert-butyl(4RS,5SR)-5-(3-chlorophenyl)-2-oxo-4-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]-1,3-oxazolidine-3-carboxylate(2.77 g, 92%) as colorless crystals.

mp 136-138° C. IR ν max^(KBr) (cm⁻¹): 1813, 1724, 1358, 1315, 1251,1195, 157, 1076, 1028 ¹H-NMR (CDCl₃) δ (ppm): 1.49 (9H, s) 2.58 (1H, dd,J=8.8, 14.4 Hz) 2.88 (1H, dd, J=4.6, 14.4 Hz), 3.21 (2H, t, J=18.4H)4.77-4.87 (1H, m), 5.64 (1H, d, J=7.0 Hz), 6.67 (2H, d, J=8.0 Hz),6.99-7.03 (3H, m), 7.12-7.19 (2H, m), 7.24-7.30 (1H, m).

10) tert-butyl(1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]ethylcarbamate

To a solution of tert-butyl(4RS,5SR)-5-(3-chlorophenyl)-2-oxo-4-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]-1,3-oxazolidine-3-carboxylate(2.66 g, 5.12 mmol) in methanol-tetrahydrofuran (20 ml-20 ml) was added1N sodium hydroxide (6.2 ml, 6.2 mmol), and the mixture was stirredovernight at room temperature. The mixture was diluted with water andextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified byrecrystallization (hexane-ethyl acetate) to give tert-butyl(1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]ethylcarbamate(2.11 g, 83%) as colorless crystals.

mp 156-157° C. IR ν max^(KBr) (cm⁻¹): 3348, 1682, 1531, 1444, 1311,1244, 1178, 1032 ¹H-NMR (CDCl₃) δ (ppm): 1.34 (9H, s) 2.59-2.79 (2H, m),3.26 (2H, t, J=18.4 Hz), 3.49 (1H, br) 4.09 (1H, br) 4.55 (1H, d, J=7.6Hz), 4.91 (1H, br) 7.08-7.20 (4H, m), 7.26-7.29 (3H, m), 7.1 (1H, s).

Example 373N-[(1RS,2SR)-1-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide

1)(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(2,2,3,3,3-pentafluoropropyl)phenyl]-1-propanol

To a solution of tert-butyl(1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]ethylcarbamate(2.00 g, 4.05 mmol) in chloroform (20 ml) was added trifluoroacetic acid(20 ml), and the mixture was stirred at room temperature for 1 hr. Themixture was concentrated under reduced pressure. To the residue wasadded water, and the mixture was basified with saturated aqueous sodiumhydrogen carbonate. The aqueous layer was extracted with ethyl acetate,dried over anhydrous magnesium sulfate, filtered and concentrated underthe reduced pressure. The residue was recrystallized from (hexane-ethylacetate) to give(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(2,2,3,3,3-pentafluoropropyl)phenyl]-1-propanol(1.08 g, 68%) as colorless crystals.

mp 109-110° C. IR ν max^(KBr) (cm⁻¹) 3000-3300, 1576, 1518, 1433, 1317,1078, 1028 ¹H-NMR (CDCl₃) δ (ppm): 1.60 (2H, br) 2.35 (1H, dd, J=10.2,13.4 Hz), 2.75 (1H, dd, J=3.0, 13.6 Hz), 3.18-3.36 (3H, m), 4.66 (1H, d,J=4.8 Hz), 7.10-7.35 (7H, m), 7.41 (1H, s).

2)N-[(1RS,2SR)-1-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide

To a solution of 4-fluoronaphthalene-1-carboxylic acid (153 mg, 0.801mmol) in N,N-dimethylformamide (5 ml) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 g,0.801 mmol) and 1-hydroxybenzotriazole monohydrate (123 mg, 0.801 mmol),and(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(2,2,3,3,3-pentafluoropropyl)phenyl]-1-propanol(0.30 g, 0.763 mmol) was finally added. The mixture was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate,washed with saturated aqueous sodium hydrogen carbonate solution, waterand saturated brine, and dried over anhydrous magnesium sulfate. Themixture was filtered using a glass filter filled with silica gel, andthe filtrate was washed with ethyl acetate and concentrated underreduced pressure. The residue was purified by recrystallization(hexane-ethyl acetate) to giveN-[(1RS,2SR)-1-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-4-fluoro-1-naphthamide(0.284 g, 66%) as colorless crystals.

mp 191-192° C. Elemental analysis for C₂₉H₂₂NO₂ClF₆ Calcd: C, 61.55; H,3.92; N, 2.47. Found: C, 61.27; H, 3.75; N, 2.45. IR ν max^(KBr) (cm⁻¹):3265, 1641, 1626, 1516, 1425, 1236, 1178, 1032 ¹H-NMR (CDCl₃) δ (ppm)2.80 (1H, dd, J=10.8, 14.1 Hz), 3.02 (1H, dd, J=4.2, 14.4 Hz), 3.29 (2H,t, J=18.0 Hz), 3.91 (1H, s) 4.70-4.77 (1H, m), 5.10 (1H, d, J=2.2 Hz),5.95 (1H, d, J=8.1 Hz), 6.90-6.96 (1H, m), 7.03 (1H, dd, J=5.4, 7.8 Hz),7.17-7.36 (7H, m), 7.43-7.56 (3H, m), 7.88 (1H, d, J=8.4 Hz), 8.07 (1H,d, J=8.4 Hz).

Example 374N-[(1RS,2SR)-1-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution of 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid(151 mg, 0.801 mmol) in N,N-dimethylformamide (5 ml) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 g,0.801 mmol) and 1-hydroxybenzotriazole monohydrate (123 mg, 0.801 mmol),and(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(2,2,3,3,3-pentafluoropropyl)phenyl]-1-propanol(0.30 g, 0.763 mmol) was finally added. The mixture was stirred at roomtemperature, overnight. The mixture was diluted with ethyl acetate,saturated aqueous sodium hydrogen carbonate solution, water andsaturated brine, and dried over anhydrous magnesium sulfate. The mixturewas filtered using a glass filter filled with silica gel, and thefiltrate was washed with ethyl acetate and concentrated under reducedpressure. The residue was purified by recrystallization (hexane-ethylacetate) to giveN-[(1RS,2SR)-1-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.284 g, 66%) as colorless crystals.

mp 176-177° C. Elemental analysis for C₃₀H₂₇NO₂ClF₅ Calcd: C, 63.89; H,4.83; N, 2.48. Found: C, 63.70; H, 4.85; N, 2.22. IR ν max^(KBr) (cm⁻¹):3281, 1635, 1518, 1433, 1315, 1197, 1030 ¹H-NMR (CDCl₃) δ (ppm)1.95-2.04 (2H, m)2.16-2.28 (2H, m), 2.64-2.68 (2H, m), 2.75 (1H, dd,J=11.1, 14.7 Hz), 2.97 (1H, dd, J=4.5, 14.7 Hz), 3.28 (2H, t, J=18.3Hz), 4.01 (1H, br) 4.62-4.71 (1H, m), 5.05 (1H, d, J=2.7 Hz), 5.74 (1H,d, J=7.8 Hz) 5.95 (1H, dt, J=5.7, 11.4 Hz), 6.29 (1H, d, J=11.7 Hz),6.88 (1H, dd, J=1.2, 7.2 Hz), 7.03 (1H, t, J=7.8 Hz), 7.0-7.36 (8H, m),7.48 (1H, s).

Example 3755-chloro-N-{(1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]ethyl}-1-naphthamide

To a solution of 5-chloronaphthalene-1-carboxylic acid (176 mg, 0.849mmol) in N,N-dimethylformamide (5 ml) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (163 mg,0.849 mmol) and 1-hydroxybenzotriazole monohydrate (130 mg, 0.849 mmol),and(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(2,2,3,3,3-pentafluoropropyl)phenyl]-1-propanol(318 mg, 0.809 mmol) was finally added. The mixture was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate,washed with saturated aqueous sodium hydrogen carbonate solution, waterand saturated brine, and dried over anhydrous magnesium sulfate. Themixturewas filtered using a glass filter filled with silica gel, and thefiltrate was washed with ethyl actate and concentrated under reducedpressure. The residue was purified by recrystallization (hexane-ethylacetate) to give5-chloro-N-{(1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]ethyl}-1-naphthamide(330 mg, 70%) as colorless crystals.

mp 216-217° C. Elemental analysis for C₂₉H₂₂NO₂Cl₂F₅ Calcd: C, 59.81; H,3.81; N, 2.41. Found: C, 59.75; H, 3.81; N, 2.41. IR ν max^(KBr) (cm⁻¹):3260, 1637, 1539, 1319, 1180, 1118, 1030 ¹H-NMR (CDCl₃) δ (ppm) 2.80(1H, dd, J=11.0, 14.4 Hz), 3.02 (1H, dd, J=4.0, 14.6 Hz), 3.30 (2H, t,J=18.2 Hz), 3.74 (1H, br) 4.72-4.84 (1H, m), 5.09 (1H, s) 5.96 (1H, d,J=8.6 Hz), 7.11-7.58 (12H, m), 7.74 (1H, d, J=8.8 Hz), 8.31 (1H, d,J=8.4 Hz).

Example 376N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-2-hydroxyethyl}-4-fluoro-1-naphthamide

1) 2-bromo-4-methyl-1-[(2-methyl-2-propenyl)oxy]benzene

To a solution of 2-bromo-p-cresol (10 ml, 82.7 mmol) inN,N-dimethylformamide (200 ml) were added potassium carbonate (17.2 g,124 mmol) and methallyl chloride (9.8 ml, 99.2 mmol), and the mixturewas stirred at 100° C. overnight. The mixture was diluted with ethylacetate, and washed with water and saturated brine. The mixture wasdried over anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=5:1) to give2-bromo-4-methyl-1-[(2-methyl-2-propenyl)oxy]benzene (19.67 g, 99%) as acolorless transparent oil.

IR ν max^(KBr) (cm⁻¹): 1658, 1604, 1494, 1452, 1377, 1286, 1251, 1230,1207, 1153 ¹H-NMR (CDCl₃) δ (ppm) 1.84 (3H, s) 2.25 (3H, s) 4.45 (2H, s)4.98-5.00 (1H, m), 5.13-5.14 (1H, m), 6.56 (1H, d, J=8.4 Hz) 6.99-7.03(1H, m), 7.35-7.36 (1H, m).

2) 3,3,5-trimethyl-2,3-dihydro-1-benzofuran

To a solution of 2-bromo-4-methyl-1-[(2-methyl-2-propenyl)oxy]benzene(5.0 g, 20.7 mmol) in toluene (100 ml) were added2,2′-azobisisobutyronitrile (1.45 g, 8.8 mmol) and tri-n-butyltinhydride (8.34 ml, 31 mmol), and the mixture was heated under refluxovernight. After completion of the reaction, the solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=1:0, 50:1) to give3,3,5-trimethyl-2,3-dihydro-1-benzofuran (3.70 g, 100%) as a colorlesstransparent oil.

IR ν max^(KBr) (cm⁻¹): 1612, 1489, 1464, 1192, 991 ¹H-NMR (CDCl₃) δ(ppm) 1.32 (6H, s) 2.29 (3H, s) 4.20 (2H, s) 6.67 (1H, d, J=8.4 Hz),6.90-6.92 (2H, m).

3) ethyl3-(3-chlorophenyl)-2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-3-oxopropionate

To a solution of 3,3,5-trimethyl-2,3-dihydro-1-benzofuran (9.42 g, 58mmol) in carbon tetrachloride (300 ml) were added2,2′-azobisisobutyronitrile (0.48 g, 2.9 mmol) and N-bromosuccinimide(10.84 g, 60.9 mmol), and the mixture was heated under reflux overnight.After cooling to room temperature, insoluble material was filtered off,and the filtrate was concentrated under reduced pressure to give abromine form.

A solution of ethyl 3-(3-chlorophenyl)-3-oxopropionate (13.15 g, 58mmol) in dimethoxyethane (100 ml) was ice-cooled and sodium hydride(60%, 2.32 g, 58 mmol) was added. The mixture was stirred for 30 min.under ice-cooling. To the mixture was added a solution of the bromineform (58 mmol) in dimethoxyethane (150 ml), and the mixture was stirredat room temperature overnight. After completion of the reaction, thereaction was quenched with 0.5N hydrochloric acid. The reaction mixturewas diluted with ethyl acetate, and washed with water and saturatedbrine. The mixture was dried over anhydrous magnesium sulfate, filtered,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (hexane:ethyl acetate=20:1, 15:1) togive ethyl3-(3-chlorophenyl)-2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-3-oxopropionate(14.04 g, 63%) as a pale-yellow oil.

IR ν max^(KBr) (cm⁻¹): 1738, 1693, 1612, 1572, 1487, 1469, 1423, 1365,1228, 1192 ¹H-NMR (CDCl₃) δ (ppm) 1.14 (3H, t, J=7.0 Hz), 1.24 (3H, s)1.28 (3H, s) 3.27 (2H, dd, J=1.8, 7.6 Hz), 4.06-4.17 (4H, q, J=7.2 Hz),6.65 (1H, d, J=8.0 Hz), 6.89-6.90 (1H, m), 6.95 (1H, dd, J=1.8, 8.0 Hz),7.36 (1H, t, J=8.0 Hz), 7.51 (1H, ddd, J=1.2, 2.2, 8.0 Hz), 7.77 (1H,dt, J=1.0, 7.6 Hz) 7.85-7.86 (1H, m).

4) ethyl(2RS,3RS)-3-(3-chlorophenyl)-2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-3-hydroxypropionate

To a suspension (140 ml) of zinc chloride (9.90 g, 72.6 mmol) in etherwas added sodium borohydride (5.50 g, 145.2 mmol) at room temperature,and the mixture was stirred as it was for 2 hrs. Insoluble material wasfiltered off, and to the filtrate was added a solution of ethyl3-(3-chlorophenyl)-2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-3-oxopropionate(14.04 g, 36.3 mmol) in ether (50 ml), and the mixture was stirred atroom temperature for 1.5 hrs. The reaction was quenched with 3Nhydrochloric acid, and the reaction mixture was diluted with ethylacetate and washed with water and saturated brine. The mixture was driedover anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=10:1, 5:1) to give ethyl(2RS,3RS)-3-(3-chlorophenyl)-2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-3-hydroxypropionate(12.07 g, 86%) as a pale-yellow oil.

IR ν max^(KBr) (cm⁻¹): 3460, 1726, 1487, 1467, 1373, 1190, 1032, 987¹H-NMR (CDCl₃) δ (ppm) 0.95 (3H, t, J=7.0 Hz), 1.27 (3H, s) 1.29 (3H, s)2.89-2.97 (3H, m), 3.18 (1H, d, J=2.4 Hz), 3.90 (2H, q, J=7.0 Hz), 4.18(2H, s) 4.98-4.99 (1H, m), 6.03 (1H, d, J=8.2 Hz), 6.78-6.84 (2H, m),7.24-7.28 (3H, m), 7.40-7.42 (1H, m).

5)(4RS,5SR)-5-(3-chlorophenyl)-4-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-1,3-oxazolidin-2-one

To a solution of ethyl(2RS,3RS)-3-(3-chlorophenyl)-2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-3-hydroxypropionate(11.44 g, 29.4 mmol) in tetrahydrofuran-ethanol (60 ml-60 ml) was added1N sodium hydroxide (60 ml, 60 mmol) at room temperature, and themixture was stirred overnight at room temperature. After completion ofthe reaction, the organic solvent was evaporated under reduced pressure.The aqueous layer was acidified with 1N hydrochloric acid, and themixture was extracted with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate and filtered, and concentrated underreduced pressure to give a colorless transparent oil. To a solution ofthe oil in tetrahydrofuran (300 ml) were added triethylamine (6.2 ml,44.1 mmol) and diphenylphosphoryl azide (7.6 ml, 35.3 mmol), and themixture was heated under reflux for 4 hrs. The solvent was evaporated,and the residue was diluted with ethyl acetate and washed with water,saturated aqueous sodium hydrogen carbonate and saturated brine. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was recrystallized fromhexane-ethyl acetate to give(4RS,5SR)-5-(3-chlorophenyl)-4-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-1,3-oxazolidin-2-one(8.11 g, 77%) as colorless crystals.

mp 183-184° C. IR ν max^(KBr) (cm⁻¹): 3271, 1759, 1489, 1236, 1194¹H-NMR (CDCl₃) δ (ppm) 1.29, 1.30 (each s, 6H) 2.15 (1H, dd, J=11.4,13.8 Hz), 2.27 (1H, dd, J=3.9, 13.8 Hz), 4.18-4.25 (3H, m) 4.98 (1H, s)5.75 (1H, d, J=7.8 Hz), 6.68 (1H, d, J=8.1 Hz) 6.74-6.79 (2H, m),7.25-7.28 (1H, m), 7.34-7.39 (3H, m).

6)(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-1-propanol

To a solution of(4RS,5SR)-5-(3-chlorophenyl)-4-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-1,3-oxazolidin-2-one(5.33 g, 14.9 mmol) in ethanol (100 ml) was added 8N aqueous sodiumhydroxide solution (9.3 ml, 74.5 mmol), and the mixture was heated underreflux for 5 hrs. After completion of the reaction, ethanol wasevaporated under reduced pressure. The residue was diluted with water,and the mixture was extracted with ethyl acetate. The organic layerswere combined, washed with saturated brine, dried over anhydrousmagnesium sulfate and filtered. The filtrate was concentrated underreduced pressure, and the residue was purified by recrystallization(hexane-ethyl acetate) to give(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-1-propanol(3.68 g, 74%) as colorless crystals.

mp 83-86° C. IR ν max^(KBr) (cm⁻¹): 3000-3300, 1597, 1574, 1487, 1469,1192, 1076, 987 ¹H-NMR (CDCl₃) δ (ppm) 1.30 (3H, s) 1.31 (3H, s) 2.28(1H, dd, J=7.5, 13.8 Hz), 2.70 (1H, dd, J=3.3, 13.8 Hz), 3.21-3.27 (1H,m) 4.20 (2H, s) 4.66 (1H, d, J=5.1 Hz), 6.69 (1H, d, J=7.8 Hz) 6.84-6.88(2H, m), 7.24-7.33 (3H, m), 7.41 (1H, s).

7)N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-2-hydroxyethyl}-4-fluoro-1-naphthamide

To a solution of 4-fluoronaphthalene-1-carboxylic acid (242 mg, 1.27mmol) in N,N-dimethylformamide (10 ml) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (243 mg,1.27 mmol) and 1-hydroxybenzotriazole monohydrate (195 mg, 1.27 mmol),and(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-1-propanol(0.40 g, 1.21 mmol) was finally added. The mixture was stirred overnightat room temperature. The mixture was diluted with ethyl acetate, washedwith saturated aqueous sodium hydrogen carbonate solution, water andsaturated brine, dried over anhydrous magnesium sulfate, and filteredusing a glass filter filled with silica gel. The filtrate was washedwith ethyl acetate and concentrated under reduced pressure. The residuewas purified by recrystallization (hexane-ethyl acetate) to giveN-{(1RS,2SR)-2-(3-chlorophenyl)-1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-2-hydroxyethyl}-4-fluoro-1-naphthamide(383 mg, 68%) as colorless crystals.

Elemental analysis for C₃₀H₂₇NO₃ClF. H₂O Calcd: C, 71.63; H, 5.81; N,2.78. Found: C, 71.28; H, 5.54; N, 2.79. IR ν max^(KBr) (cm⁻¹): 3281,1641, 1626, 1518, 1487, 1464, 1425, 1261, 1236, 1194 ¹H-NMR (CDCl₃) δ(ppm) 1.22 (3H, s) 1.27 (3H, s) 2.71 (1H, dd, J=11.1, 14.7 Hz), 3.00(1H, dd, J=4.2, 14.4 Hz), 4.12 (1H, d, J=4.2 Hz), 4.21 (2H, d, J=0.9Hz), 4.69-4.78 (1H, m), 5.08-5.10 (1H, m), 5.83 (1H, d, J=7.5 Hz), 6.72(1H, d, J=8.4 Hz) 6.91-7.02 (3H, m), 7.16 (1H, dd, J=5.4, 7.8 Hz),7.27-7.38 (3H, m) 7.45-7.57 (3H, m), 7.80 (1H, d, J=8.1 Hz), 8.07 (1H,d, J=7.8 Hz).

Example 377N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-2-hydroxyethyl}-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution of 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid(239 mg, 1.27 mmol) in N,N-dimethylformamide (5 ml) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (243 mg,1.27 mmol) and 1-hydroxybenzotriazole monohydrate (195 mg, 1.27 mmol),and(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-1-propanol(0.40 g, 1.21 mmol) was finally added. The mixture was stirred overnightat room temperature. The mixture was diluted with ethyl acetate, washedwith saturated aqueous sodium hydrogen carbonate solution, water andsaturated brine, dried over anhydrous magnesium sulfate, and filteredusing a glass filter filled with silica gel. The filtrate was washedwith ethyl acetate and concentrated under reduced pressure. The residuewas purified by recrystallization (hexane-ethyl acetate) to giveN-{(1RS,2SR)-2-(3-chlorophenyl)-1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-2-hydroxyethyl}-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(326 mg, 54%) as colorless crystals.

mp 149-150° C. Elemental analysis for C₃₁H₃₂NO₃Cl.0.5H₂O Calcd: C,72.86; H, 6.51; N, 2.74. Found: C, 73.04; H, 6.26; N, 3.04. IR νmax^(KBr) (cm⁻¹): 3304, 1635, 1514, 1487, 1192, 1076, 987, 910 ¹H-NMR(CDCl₃) δ (ppm) 1.28 (6H, s) 1.98-2.01 (2H, m), 2.16-2.21 (2H, m),2.58-2.69 (3H, m), 2.87-2.95 (1H, m), 4.20 (2H, s) 4.62 (1H, br) 5.00(1H, s) 5.71 (1H, d, J=7.4 Hz), 5.89-6.00 (1H, m) 6.26 (1H, d, J=11.8Hz), 6.68 (1H, d, J=8.8 Hz), 6.88-7.16 (5H, m), 7.26-7.30 (3H, m), 7.46(1H, s)

Example 3785-chloro-N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-2-hydroxyethyl}-1-naphthamide

To a solution of 5-chloronaphthalene-1-carboxylic acid (260 mg, 1.26mmol) in N,N-dimethylformamide (5 ml) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (242 mg,1.26 mmol) and 1-hydroxybenzotriazole monohydrate (193 mg, 1.26 mmol),and(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-1-propanol(0.40 g, 1.20 mmol) was finally added. The mixture was stirred overnightat room temperature. The mixture was diluted with ethyl acetate, washedwith saturated aqueous sodium hydrogen carbonate, water and saturatedbrine, dried over anhydrous magnesium sulfate, and filtered using aglass filter filled with silica gel. The filtrate was washed with ethylacetate and concentrated under reduced pressure. The residue waspurified by recrystallization (hexane-ethyl acetate) to give5-chloro-N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-2-hydroxyethyl}-1-naphthamide(473 mg, 76%) as colorless crystals.

mp 191-192° C. Elemental analysis for C₃₀H₂₇NO₃Cl₂ Calcd: C, 69.23; H,5.23; N, 2.69. Found: C, 69.02; H, 5.04; N, 2.71. IR ν max^(KBr) (cm⁻¹):3271, 1639, 1572, 1520, 1487, 1194, 908 ¹H-NMR (CDCl₃)δ (ppm) 1.23 (3H,s) 1.26 (3H, s) 2.70 (1H, dd, J=11.0, 14.6 Hz), 2.99 (1H, dd, J=4.4,14.8 Hz), 4.21 (2H, s) 4.71-4.78 (1H, m), 5.07 (1H, d, J=3.2 Hz), 5.86(1H, d, J=8.2 Hz), 6.71 (1H, d, J=8.8 Hz), 6.90-6.93 (2H, m), 7.22-7.64(9H, m), 8.31 (1H, d, J=8.4 Hz).

Example 379N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-2-hydroxyethyl}-4-fluoro-1-naphthamide

1) 2,2-dimethyl-1-(4-methylphenyl)-1-propanone

To a suspension (200 ml) of magnesium (7.14 g, 294 mmol) in ether in athree necked flask was added dropwise a solution of p-bromotoluene (34ml, 276 mmol) in ether (100 ml), and the mixture was heated under refluxfor 1.5 hrs. Thereafter, to the mixture was added a solution oftrimethylacetonitrile (25 ml, 226 mmol) in ether (100 ml), and themixture was stirred for 2 hrs. The mixture was then ice-cooled. To themixture was added dropwise 6N hydrochloric acid, and the mixture wasstirred at room temperature for 30 min. The mixture was diluted withether, and washed with water and saturated brine. The mixture was driedover anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:0, 10:1) to give2,2-dimethyl-1-(4-methylphenyl)-1-propanone (10.94 g, 27%) as acolorless transparent oil.

IR ν max^(KBr) (cm⁻¹): 1672, 1608, 1477, 1396, 1365, 1278, 960 ¹H-NMR(CDCl₃) δ (ppm)1.35 (9H, s) 2.38 (3H, s) 7.20 (2H, d, J=8.1 Hz), 7.66(2H, d, J=8.4 Hz).

2) 1-(1,1-difluoro-2,2-dimethylpropyl)-4-methylbenzene

To a flask containing 2,2-dimethyl-1-(4-methylphenyl)-1-propanone (4.69g, 26.6 mmol) was added dropwise bis(2-methoxyethyl)aminosulfurtrifluoride (10 g; 45.2 mmol), and the mixture was stirred at 80 to 85°C. overnight. The reaction mixture was poured into saturated aqueoussodium hydrogen carbonate, and the mixture was extracted with ethylacetate. The mixture was dried over anhydrous magnesium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane) to give1-(1,1-difluoro-2,2-dimethylpropyl)-4-methylbenzene (5.16 g, 77%) as acolorless transparent oil.

IR ν max^(KBr) (cm⁻¹): 1618, 1518, 1485, 1464, 1308, 1286, 1259, 1209,1093, 1072, 976 ¹H-NMR (CDCl₃) δ (ppm) 1.02 (9H, s) 2.37 (3H, s)7.15-7.19 (2H, m) 7.31 (2H, d, J=8.4 Hz).

3) ethyl3-(3-chlorophenyl)-2-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-3-oxopropionate

To a solution of 1-(1,1-difluoro-2,2-dimethylpropyl)-4-ethylbenzene(4.52 g, 22.8 mmol) in carbon tetrachloride (150 ml) were added2,2′-azobisisobutyronitrile (188 mg, 1.14 mmol) and N-bromosuccinimide(4.06 g, 22.8 mmol), and the mixture was heated under reflux overnight.After cooling to room temperature, insoluble material was filtered off,and the residue was concentrated under reduced pressure to give abromine form, which was directly used in the next reaction.

A solution of ethyl 3-(3-chlorophenyl)-3-oxopropionate (5.17 g, 22.8mmol) in dimethoxyethane (60 ml) was ice-cooled. To the solution wasadded sodium hydride (60%, 0.92 g, 22.8 mmol) under ice-cooling, and themixture was stirred for 15 min. To the mixture was added a solution ofthe bromine form (22.8 mmol) in dimethoxyethane (40 ml), and the mixturewas stirred overnight at room temperature. After completion of thereaction, the reaction was quenched with 1N hydrochloric acid, and themixture was diluted with ethyl acetate and washed with water andsaturated brine. The mixture was dried over anhydrous magnesium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=20:1,15:1) to give ethyl3-(3-chlorophenyl)-2-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-3-oxopropionate(7.44 g, 77%) as a pale-yellow oil.

IR ν max^(KBr) (cm⁻¹): 1736, 1691, 1570, 1483, 1425, 1367, 1259, 1093,1072 ¹H-NMR (CDCl₃) δ (ppm) 0.99 (9H, s) 1.12 (3H, t, J=6.9 Hz) 3.34(2H, d, J=7.5 Hz), 3.96-4.15 (2H, m), 4.56 (1H, t, J=7.2 Hz), 7.21-7.45(5H, m), 7.50-7.55 (1H, m), 7.78-7.90 (1H, m), 7.90-7.92 (1H, m).

4) ethyl(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]propionate

To a suspension (70 ml) of zinc chloride (4.94 g, 36.2 mmol) in etherwas added sodium borohydride (2.74 g, 72.4 mmol) at room temperature,and the mixture was stirred as it was for 2 hrs. Insoluble material wasfiltered off. To the filtrate was added a solution of ethyl3-(3-chlorophenyl)-2-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-3-oxopropionate(7.59 g, 18.1 mmol) in ether (50 ml), and the mixture was stirred atroom temperature for 1 hr. The reaction was quenched with 1Nhydrochloric acid, and the mixture was diluted with ethyl acetate,washed with water and saturated brine. The mixture was dried overanhydrous magnesium sulfate, filtered and concentrated. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=15:1,10:1, 5:1) to give ethyl(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]propionate(6.12 g, 80%) as a pale-yellow oil.

IR ν max^(KBr) (cm⁻¹): 3454, 1712, 1616, 1597, 1576, 1483, 1398, 1371,1398, 1286, 1259, 1190 ¹H-NMR (CDCl₃) δ (ppm) 0.94 (3H, t, J=7.2 Hz),1.00 (9H, s) 2.90-3.04 (2H, m), 3.11 (1H, d, J=1.8 Hz), 3.90 (2H, q,J=7.0 Hz), 5.03 (1H, d, J=2.2 Hz), 7.09 (2H, d, J=8.0 Hz) 7.25-7.29 (5H,m), 7.42 (1H, s).

5)(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]propionicacid

To a solution of ethyl(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]propionate(5.88 g, 13.8 mmol) in tetrahydrofuran-ethanol (30 ml—30 ml) was added1N sodium hydroxide (28 ml, 28 mmol) at room temperature, and themixture was stirred overnight at room temperature. After completion ofthe reaction, the organic solvent was evaporated under reduced pressure.The aqueous layer was acidified with 1N hydrochloric acid, and themixture was extracted with ethyl acetate. The organic layer was driedover anhydrous magnesium sulfate. The mixture was filtered, and thefiltrate was concentrated under reduced pressure. The residue wasrecrystallized from hexane-ethyl acetate to give(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]propionicacid (4.24 g, 77%) as colorless crystals.

mp 141-142° C. IR ν max^(KBr) (cm⁻¹) 2500-3300, 1709, 1599, 1574, 1483,1413, 1398, 1369, 1286, 1259 ¹H-NMR (CDCl₃) δ (ppm) 0.99 (9H, s)2.90-3.05 (3H, m), 5.10 (1H, d, J=3.6 Hz), 7.07 (2H, d, J=8.1 Hz),7.25-7.28 (5H, m), 7.42 (1H, s).

6)(4RS,5SR)-5-(3-chlorophenyl)-4-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-1,3-oxazolidin-2-one

To a solution of(2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]propionicacid (4.09 g, 10.3 mmol) in tetrahydrofuran (100 ml) were addedtriethylamine (2.16 ml, 15.45 mmol) and diphenylphosphoryl azide (2.67ml, 12.36 mmol), and the mixture was heated under reflux for 4 hrs. Thesolvent was evaporated, and the residue was diluted with ethyl acetate,and washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried overanhydrous magnesium sulfate, filtered, and concentrated under reducedpressure. The residue was recrystallized from hexane-ethyl acetate togive(4RS,5SR)-5-(3-chlorophenyl)-4-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-1,3-oxazolidin-2-one(3.97 g, 98%) as colorless crystals.

mp 188-190° C. IR ν max^(KBr) (cm⁻¹): 3246, 1739, 1437, 1369, 1286,1238, 1078 ¹H-NMR (CDCl₃) δ (ppm) 1.01 (9H, s) 2.27 (1H, dd, J=10.8,13.1 Hz), 2.36 (1H, dd, J=4.2, 12.8 Hz), 4.23-4.31 (1H, m), 5.09 (1H, s)5.77 (1H, d, J=8.1 Hz), 7.05 (2H, d, J=8.1 Hz) 7.24-7.29 (1H, m),7.32-7.38 (5H, m).

7)(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(1,1-difluoro-2,2-dimethylpropyl)phenyl]-1-propanol

To a solution of(4RS,5SR)-5-(3-chlorophenyl)-4-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-1,3-oxazolidin-2-one(3.82 g, 9.70 mmol) in ethanol (100 ml) was added 8N aqueous sodiumhydroxide solution (6.1 ml, 48.5 mmol), and the mixture was heated underreflux for 4 hrs. After completion of the reaction, ethanol wasevaporated under reduced pressure. The residue was diluted with water,and the mixture was extracted with ethyl acetate. The organic layerswere combined, washed with saturated brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by recrystallization (hexane-ethyl acetate) togive(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(1,1-difluoro-2,2-dimethylpropyl)phenyl]-1-propanol(2.56 g, 72%) to give colorless crystals.

mp 105-107° C. IR ν max^(KBr) (cm⁻¹): 3352, 1597, 1483, 1286, 1259,1093, 1068, 1037, 1008, 978 ¹H-NMR (CDCl₃) δ (ppm) 1.02 (9H, s) 2.38(1H, dd, J=10.6, 13.6 Hz), 2.80 (1H, dd, J=2.8, 13.2 Hz), 3.27-3.36 (1H,m), 4.68 (1H, d, J=4.8 Hz), 7.15 (2H, d, J=8.2 Hz), 7.26-7.35 (5H, m),7.42 (1H, s).

8)N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-2-hydroxyethyl}-4-fluoro-1-naphthamide

To a solution of 4-fluoronaphthalene-1-carboxylic acid (216 mg, 1.15mmol) in N,N-dimethylformamide (5 ml) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (220 mg,1.15 mmol) and 1-hydroxybenzotriazole monohydrate (176 mg, 1.15 mmol),and(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(1,1-difluoro-2,2-dimethylpropyl)phenyl]-1-propanol(0.40 g, 1.09 mmol) was finally added. The mixture was stirred overnightat room temperature. The mixture was diluted with ethyl acetate, washedwith saturated aqueous sodium hydrogen carbonate solution, water andsaturated brine, dried over anhydrous magnesium sulfate, and filteredusing a glass filter filled with silica gel. The filtrate was washedwith ethyl acetate and concentrated under reduced pressure. The residuewas purified by recrystallization (hexane-ethyl acetate) to giveN-{(1RS,2SR)-2-(3-chlorophenyl)-1-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-2-hydroxyethyl}-4-fluoro-1-naphthamide(289 mg, 49%) as colorless crystals.

mp 104-106° C. IR ν max^(KBr) (cm⁻¹): 3244, 1639, 1626, 1599, 1516,1425, 1286, 1261, 1091, 1072, 1008, 978 ¹H-NMR (CDCl₃) δ (ppm) 1.01 (9H,s) 2.82 (1H, dd, J=11.0, 14.4 Hz), 3.03 (1H, dd, 4.4, 14.4 Hz), 3.85(1H, s) 4.72-4.81 (1H, m), 5.10 (1H, d, J=3.4 Hz), 5.98 (1H, d, J=8.4Hz), 6.93 (1H, dd, J=7.6, 9.8 Hz), 7.10 (1H, dd, J=5.0, 7.6 Hz),7.19-7.56 (10H, m), 7.75 (1H, d, J=7.6 Hz), 8.06 (1H, d, J=8.0 Hz).

Example 380N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-2-hydroxyethyl}-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide

To a solution of 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid(216 mg, 1.15 mmol) in N,N-dimethylformamide (5 ml) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (220 mg,1.15 mmol) and 1-hydroxybenzotriazole monohydrate (176 mg, 1.15 mmol),and(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(1,1-difluoro-2,2-dimethylpropyl)phenyl]-1-propanol(0.40 g, 1.09 mmol) was finally added. The mixture was stirred overnightat room temperature. The mixture was diluted with ethyl acetate, washedwith saturated aqueous sodium hydrogen carbonate solution, water andsaturated brine, dried over anhydrous magnesium sulfate, and filteredusing a glass filter filled with silica gel. The filtrate was washedwith ethyl acetate, and concentrated under reduced pressure. The residuewas purified by recrystallization (hexane-ethyl acetate) to giveN-{(1RS,2SR)-2-(3-chlorophenyl)-1-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-2-hydroxyethyl}-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(316 mg, 54%) as colorless crystals.

mp 119-120° C. IR ν max^(KBr) (cm⁻¹): 3265, 1635, 1516, 1485, 1286, 1259¹H-NMR (CDCl₃) δ (ppm) 1.28 (6H, s) 1.98-2.01 (2H, m), 2.16-2.21 (2H,m), 2.58-2.69 (3H, m), 2.87-2.95 (1H, m), 4.20 (2H, s) 4.62 (1H, br)5.00 (1H, s) 5.71 (1H, d, J=7.4 Hz), 5.89-6.00 (1H, m) 6.26 (1H, d,J=11.8 Hz), 6.68 (1H, d, J=8.8 Hz), 6.88-7.16 (5H, m), 7.26-7.30 (3H,m), 7.46 (1H, s)

Example 3815-chloro-N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-2-hydroxyethyl}-1-naphthamide

To a solution of 5-chloronaphthalene-1-carboxylic acid (238 mg, 1.15mmol) in N,N-dimethylformamide (5 ml) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (220 mg,1.15 mmol) and 1-hydroxybenzotriazole monohydrate (176 mg, 1.15 mmol),and(1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(1,1-difluoro-2,2-dimethylpropyl)phenyl]-1-propanol(0.40 g, 1.09 mmol) was finally added. The mixture was stirred overnightat room temperature. The mixture was diluted with ethyl acetate, washedwith saturated aqueous sodium hydrogen carbonate solution, water andsaturated brine, dried over anhydrous magnesium sulfate, and filteredusing a glass filter filled with silica gel. The filtrate was washedwith ethyl acetate and concentrated under reduced pressure. The residuewas purified by recrystallization (hexane-ethyl acetate) to give5-chloro-N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-2-hydroxyethyl}-1-naphthamide(252 mg, 42%) as colorless crystals.

mp 99-101° C. IR ν max^(KBr) (cm⁻¹): 3260, 1635, 1521, 1286, 1093, 1072,1037, 1008, 978, 908 ¹H-NMR (CDCl₃) δ (ppm) 1.01 (9H, s) 2.79 (1H, dd,J=11.1, 14.4 Hz), 3.02 (1H, dd, J=3.6, 14.1 Hz), 4.74-4.82 (1H, m), 5.07(1H, d, J=3.6 Hz), 6.02 (1H, d, J=8.7 Hz), 7.15-7.41 (10H, m), 7.53-7.57(3H, m), 8.28 (1H, d, J=8.7 Hz).

Example 382(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a]cyclohepten-1-ylcarbonyl)amino]-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propylacetate

A mixture ofN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.359 g, 0.675 mmol), acetic anhydride (2 ml) and pyridine (5 ml) wasstirred at 100° C. overnight. The solvent of the reaction solution wasevaporated under reduced pressure and the obtained residue was purifiedby silica gel column chromatography (ethyl acetate). Crystallizationfrom diisopropyl ether-hexane gave the objective substance.

white crystals yield 0.347 g, 90% mp 176-177° C.; ¹H-NMR (CDCl₃, 200MHz) δ 1.91-2.05 (2H, m), 2.15 (3H, s), 2.13-2.32 (2H, m), 2.63-2.66(2H, m), 2.71 (1H, dd, J=10.2 Hz, 15.2 Hz), 3.07 (1H, dd, J=4.3 Hz, 14.7Hz), 4.89-5.03 (1H, m), 5.51 (1H, d, J=9.6 Hz), 5.89 (1H, tt, J=2.9 Hz,53.0 Hz), 5.81-6.06 (3H, m), 6.82 (1H, dd, J=2.0 Hz, 7.2 Hz), 6.97-7.15(7H, m), 7.32 (1H, t, J=7.9 Hz), 7.41 (2H, dd, J=5.4 Hz, 8.6 Hz); IR(KBr) 3241, 1746, 1642, 1512, 1275, 1236, 1113, 772 cm⁻¹; Anal. Calcdfor C₃₁H₂₈F₅NO₄: C, 64.92; H, 4.92; N, 2.44. Found: C, 64.87; H, 4.84;N, 2.30.

Example 383(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a]cyclohepten-1-ylcarbonyl)amino]-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propylmethyl succinate

A solution ofN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.301 g, 0.566 mmol), monomethyl succinate monochloride (0.10 ml, 0.85mmol) and 4-N,N-dimethylaminopyridine (0.14 g, 1.13 mmol) inacetonitrile (15 ml) was stirred at 80° C. for 2 hrs. The solvent of thereaction solution was evaporated under reduced pressure, and theobtained residue was purified by silica gel column chromatography(hexane/ethyl acetate=3/1−2/1) to give the objective substance.

white solid yield 0.365 g, 100%

Recrystallization from ethyl acetate-hexane gave white crystals.

mp 170-171° C.; ¹H-NMR (CDCl₃, 300 MHz) δ 1.92-2.00 (2H, m), 2.18-2.24(2H, m), 2.61-2.81 (7H, m), 3.02 (1H, dd, J=4.2 Hz, 14.4 Hz), 3.50 (3H,s), 4.87-4.97 (1H, m), 5.85 (1H, td, J=5.2 Hz, 11.9 Hz), 5.89 (1H, tt,J=2.8 Hz, 53.0 Hz), 5.90 (1H, d, J=9.9 Hz), 6.03 (1H, d, J=12.0 Hz),6.16 (1H, d, J=4.8 Hz), 6.86 (1H, dd, J=1.5 Hz, 7.5 Hz), 6.99-7.13, (7H,m), 7.30 (1H, t, J=8.0 Hz), 7.43 (2H, dd, J=5.3 Hz, 8.6 Hz); IR (KBr)3239, 1742, 164.0, 1512, 1223, 1165, 1128 cm⁻¹; Anal. Calcd forC₃₄H₃₂F₅NO₆: C, 63.25; H, 5.00; N, 2.17. Found: C, 63.21; H, 5.03; N,2.13.

Example 384(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a]cyclohepten-1-ylcarbonyl)amino]-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propylhydrogen succinate

To a solution ofN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.566 g, 1.065 mmol) and succinic chloride (0.41 g, 2.66 mmol) inacetonitrile (30 ml) was added 4-N,N-dimethylaminopyridine (0.26 g, 2.13mmol), and the mixture was stirred at 70° C. for 3 hrs. After coolingthe reaction solution to room temperature, water (30 ml) was added, andthe mixture was stirred as it was for 0.5 hr. The reaction solution wasacidified with diluted hydrochloric acid, and extracted twice with ethylacetate. The recovered organic layer was dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained crude product was purified by silica gel column chromatography(hexane/ethyl acetate=1/1-ethyl acetate). Crystallization fromdiisopropyl ether-hexane gave the objective substance.

pale-brown powder yield 0.466 g, 69% mp 154-155° C.; ¹H-NMR (CDCl₃, 300MHz) δ 1.92-2.01 (2H, m), 2.17-2.23 (2H, m), 2.58-2.77 (7H, m), 3.04(1H, dd, J=3.8 Hz, 14.3 Hz), 4.89-4.99 (1H, m), 5.71 (1H, d, J=9.3 Hz),5.85 (1H, td, J=5.1 Hz, 11.7 Hz), 5.89 (1H, tt, J=2.9 Hz, 53.1 Hz), 6.00(1H, d, J=11.7 Hz), 6.06, (1H, d, J=5.4 Hz), 6.84 (1H, dd, J=1.4 Hz, 7.7Hz), 6.98-7.13 (7H, m), 7.30 (1H, t, J=7.8 Hz), 7.41 (2H, dd, J=5.3 Hz,8.6 Hz); IR (KBr) 3243, 3067, 2940, 1734, 1640, 1512, 1211, 1155, 1123cm⁻¹; Anal. Calcd for C₃₃H₃₀F₅NO₆.0.5H₂O: C, 61.87; H, 4.88; N, 2.19.Found: C, 61.78; H, 4.77; N, 2.15.

Example 385 sodium(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a]cyclohepten-1-ylcarbonyl)amino]-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propylsuccinate

To a solution of(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a]cyclohepten-1-ylcarbonyl)amino]-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propylhydrogen succinate (165 mg, 0.261 mmol) in tetrahydrofuran (2 ml) wasadded 1N aqueous sodium hydroxide solution (0.26 ml, 0.26 mmol), and themixture was stirred at room temperature for 5 min. The solvent of thereaction solution was evaporated under reduced pressure, and theobtained residue was crystallized from ethanol-hexane to give theobjective substance.

pale-brown powder yield 130 mg, 76% mp 165-170° C.; ¹H-NMR (CDCl₃, 300MHz) δ 1.92-2.00 (2H, m), 2.17-2.23 (2H, m), 2.60-2.75 (7H, m), 3.03(1H, dd, J=3.9 Hz, 14.1 Hz), 4.90-5.00 (1H, m), 5.66 (1H, d, J=9.6 Hz),5.85 (1H, td, J=5.3 Hz, 10.5 Hz), 5.89 (1H, tt, J=2.9 Hz, 53.0 Hz), 6.01(1H, d, J=12.0 Hz), 6.04 (1H, d, J=5.1 Hz), 6.83 (1H, dd, J=1.5 Hz, 7.5Hz), 6.99-7.13 (7H, m), 7.29 (1H, t, J=7.8 Hz), 7.40 (2H, dd, J=5.3 Hz,8.9 Hz); IR (KBr) 3400-2900, 1730, 1640, 1534, 1514, 1200, 1159, 1128cm⁻¹; Anal. Calcd for C₃₃H₂₉F₅NO₆Na.2.0H₂O: C, 57.48; H, 4.82; N, 2.03.Found: C, 57.49; H, 4.46; N, 1.88.

Example 386 N-(tert-butoxycarbonyl)glycine(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a]cyclohepten-1-ylcarbonyl)amino]-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propylester

A solution ofN-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide(0.304 g, 0.572 mmol), BOC-glycine (0.12 g, 0.69 mmol),4-N,N-dimethylaminopyridine (0.14 g, 1.14 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.16 g,0.86 mmol) in acetonitrile (10 ml) was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, and dried overanhydrous magnesium sulfate. After passing through silica gel, thesolvent was evaporated under reduced pressure to give the objectivesubstance.

white solid yield 0.411 g, 100%

Crystallization from diisopropyl ether-hexane gave white powder.

mp 151-152° C.; ¹H-NMR (CDCl₃, 300 MHz) δ 1.41 (9H, s), 1.93-2.01 (2H,m), 2.18-2.24 (2H, m), 2.66 (2H, t, J=5.9 Hz), 2.70 (1H, dd, J=10.5 Hz,14.4 Hz), 3.04 (1H, dd, J=4.1 Hz, 14.3 Hz), 3.91-4.06 (2H, m), 4.91-5.00(1H, m), 5.07 (1H, br t, J=4.5 Hz), 5.68 (1H, d, J=9.9 Hz), 5.86 (1H,td, J=5.4 Hz, 12.0 Hz), 5.89 (1H, tt, J=2.9 Hz, 53.1 Hz), 6.02 (1H, d,J=11.7 Hz), 6.11 (1H, d, J=5.4 Hz), 6.87 (1H, d, J=7.2 Hz), 7.01-7.13(7H, m), 7.31 (1H, t, J=8.0 Hz), 7.41 (2H, dd, J=5.4 Hz, 8.7 Hz); IR(KBr) 3370, 3310, 2936, 1750, 1684, 1638, 1512, 1225, 1196, 1157, 1125cm⁻¹; Anal. Calcd for C₃₆H₃₇F₅N₂O₆: C, 62.79; H, 5.42; N, 4.07. Found:C, 62.60; H, 5.49; N, 4.00.

Example 387 glycine(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a]cyclohepten-1-ylcarbonyl)amino]-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propylester hydrochloride

A mixture of N-(tert-butoxycarbonyl)glycine(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a]cyclohepten-1-ylcarbonyl)amino]-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propylester (0.351 g, 0.510 mmol), conc. hydrochloric acid (0.3 ml) andmethanol (8 ml) was stirred at 50° C. for 1 hr. The solvent of thereaction solution was evaporated under reduced pressure, and theobtained residue was crystallized from diethyl ether to give theobjective substance.

white powder yield 0.270 g yield 85% mp 174-177° C. (dec.); ¹H-NMR(CD₃OD, 300 MHz) δ 1.88-1.96 (2H, m), 2.19-2.24 (2H, m), 2.63-2.72 (3H,m), 3.24 (1H, dd, J=3.3 Hz, 14.1 Hz), 3.90 (1H, d, J=17.1 Hz), 3.99 (1H,d, J=17.1 Hz), 4.86-4.98 (1H, m), 5.69-5.79 (2H, m), 6.04 (1H, d, J=6.9Hz), 6.24 (1H, tt, J=2.9 Hz, 52.6 Hz), 6.59 (1H, dd, J=1.2 Hz, 7.5 Hz),7.00 (1H, t, J=7.4 Hz), 7.10-7.17 (5H, m), 7.23 (1H, d, J=7.8 Hz), 7.38(1H, t, J=7.8 Hz), 7.55 (2H, dd, J=5.3 Hz, 8.9 Hz); IR (KBr) 3283,3100-2800, 1744, 1640, 1514, 1271, 1233, 1200, 1125 cm⁻¹; Anal. Calcdfor C₃₁H₃₀ClF₅N₂O₄.0.5H₂O: C, 58.72; H, 4.93; N, 4.42. Found: C, 58.46;H, 4.84; N, 4.51.

Example 388(1RS,2SR)-2-[(4-fluoro-1-naphthoyl)amino]-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propylhydrogen succinate

To a solution of4-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]naphthalene-1-carboxamide(0.664 g, 1.245 mmol) and succinic chloride (0.48 g, 3.11 mmol) inacetonitrile (30 ml) was added 4-N,N-dimethylaminopyridine (0.30 g, 2.49mmol), and the mixture was stirred at 70° C. for 3 hrs. After coolingthe reaction solution to room temperature, water (30 ml) was added, andthe mixture was stirred as it was for 0.5 hr. The reaction solution wasacidified with dilute hydrochloric acid, and extracted twice with ethylacetate. The recovered organic layer was dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained crude product was purified by silica gel column chromatography(hexane/ethyl acetate=1/1-ethyl acetate). Crystallization fromdiisopropyl ether-hexane gave the objective substance.

pale-brown powder yield 0.438 g, 56% mp 181-182° C.; ¹H-NMR(CDCl₃-DMSO-d₆, 300 MHz) δ 2.70-2.76 (4H, m), 2.84 (1H, dd, J=11.7 Hz,14.4 Hz), 3.07 (1H, dd, J=3.9 Hz, 14.4 Hz), 4.93-5.02 (1H, m), 5.94 (1H,tt, J=2.9 Hz, 53.0 Hz), 6.27 (1H, d, J=5.4 Hz), 7.01-7.32 (8H, m),7.40-7.53 (5H, m), 8.03 (1H, d, J=9.0 Hz); IR (KBr) 3308, 3100-2800,1740, 1723, 1640, 1624, 1530, 1516, 1235, 1179, 1119 cm⁻¹; Anal. Calcdfor C₃₂H₂₅F₆NO₆: C, 60.67; H, 3.98; N, 2.21. Found: C, 60.37; H, 3.76;N, 2.05.

Example 389 sodium(1RS,2SR)-2-[(4-fluoro-1-naphthoyl)amino]-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propylsuccinate

To a solution of(1RS,2SR)-2-[(4-fluoro-1-naphthoyl)amino]-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propylhydrogen succinate (242 mg, 0.382 mmol) in tetrahydrofuran (2 ml) wasadded 1N aqueous sodium hydroxide solution (0.38 ml, 0.38 mmol), and themixture was stirred at room temperature for 5 min. The solvent of thereaction solution was evaporated under reduced pressure, and theobtained residue was crystallized from ethanol-hexane to give theobjective substance.

pale-brown powder yield 165 mg, 66% mp 192-198° C.; ¹H-NMR (DMSO-d₆, 300MHz) δ 2.42-2.64 (4H, m), 2.81 (1H, dd, J=11.7 Hz, 13.2 Hz), 3.08 (1H,dd, J=2.1 Hz, 13.5 Hz), 4.68-4.79 (1H, m), 5.93 (1H, d, J=6.9 Hz), 6.73(1H, tt, J=2.9 Hz, 51.8 Hz), 7.08-7.42 (10H, m), 7.50 (2H, dd, J=5.7 Hz,8.4 Hz), 7.58 (1H, t, J=7.4 Hz), 8.01 (1H, d, J=8.7 Hz), 8.73 (1H, d,J=9.3 Hz); IR (KBr) 3304, 1738, 1842, 1574, 1530, 1514, 1119 cm⁻¹; Anal.Calcd for C₃₂H₂₄F₆NO₆Na.1.0H₂O: C, 57.06; H, 3.89; N, 2.08. Found: C,56.79; H, 3.86; N, 1.90.

Example 390 N-(tert-butoxycarbonyl)glycine(1RS,2SR)-2-[(4-fluoro-1-naphthoyl)amino]-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propylester

A solution of4-fluoro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]naphthalene-1-carboxamide(0.486 g, 0.911 mmol), BOC-glycine (0.19 g, 1.09 mmol),4-N,N-dimethylaminopyridine (0.22 g, 1.82 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g,1.37 mmol) in acetonitrile (20 ml) was stirred overnight at roomtemperature. The reaction solution was diluted with ethyl acetate,washed with aqueous sodium hydrogen carbonate solution, dried overanhydrous magnesium sulfate and passed through silica gel. The solventwas evaporated under reduced pressure. The obtained residue wascrystallized from diisopropyl ether-hexane to give the objectivesubstance

white powder yield 0.582 g, 93% mp 126-127° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.33 (9H, s), 2.81 (1H, dd, J=11.0 Hz, 14.6 Hz), 3.10 (1H, dd, J=3.9Hz, 14.4 Hz), 3.93 (1H, dd, J=6.0 Hz, 17.4 Hz), 4.04 (1H, dd, J=5.9 Hz,1.9 Hz), 4.98-5.09 (2H, m), 5.88 (1H, tt, J=2.8 Hz, 53.2 Hz), 6.08 (1H,d, J=9.9 Hz), 6.26 (1H, d, J=3.9 Hz), 7.00 (1H, dd, J=7.8 Hz, 9.9 Hz),7.08-7.19 (6H, m), 7.32 (1H, t, J=8.0 Hz), 7.40-7.54 (4H, m), 7.62 (1H,d, J=7.8 Hz), 8.06 (1H, d, J=7.8 Hz); IR (KBr) 3360, 3297, 2982, 1746,1682, 1642, 1530, 1514, 1227, 2300, 1161, 1125 cm⁻; Anal. Calcd forC₃₅H₃₂F₆N₂O₆: C, 60.87; H, 4.67; N, 4.06. Found: C, 60.73; H, 4.65; N,4.05.

Example 391 glycine(1RS,2SR)-2-[(4-fluoro-1-naphthoyl)amino]-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propylester hydrochloride

A mixture of N-(tert-butoxycarbonyl)glycine(1RS,2SR)-2-[(4-fluoro-1-naphthoyl)amino]-1-(4-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propylester (0.404 g, 0.585 mmol), conc. hydrochloric acid (0.4 ml) andmethanol (6 ml) was stirred at 50° C. for 1 hr. The solvent of thereaction solution was evaporated under reduced pressure, and theobtained residue was crystallized from diethyl ether to give theobjective substance.

white powder yield 0.331 g, 90%

mp 209-212° C. (dec.); ¹H-NMR (CD₃OD, 300 MHz) δ 2.78 (1H, dd, J=11.9Hz, 14.3 Hz), 3.33 (1H, dd, J=3.9 Hz, 14.3 Hz), 3.95 (1H, d, J=17.4 Hz),4.04 (1H, d, J=17.4 Hz), 4.98-5.06 (1H, m), 6.08 (1H, d, J=7.5 Hz),6.249 (1H, tt, J=2.9 Hz, 52.7 Hz), 7.00 (1H, dd, J=5.4 Hz, 8.1 Hz), 7.07(1H, dd, J=7.7 Hz, 10.1 Hz), 7.14-7.28 (6H, m), 7.36-7.41 (2H, m),7.51-7.61 (3H, m), 8.03 (1H, d, J=8.4 Hz); IR (KBr) 3301, 3100-2800,1740, 1644, 1514, 1275, 1235, 1206, 1121 cm⁻¹; Anal. Calcd forC₃₀H₂₅ClF₆N₂O₄.0.5H₂O: C, 5.6.66; H, 4.12; N, 4.40. Found: C, 56.81; H,4.35; N, 4.62.

Example 392(1RS,2SR)-3-(4-tert-butylphenyl)-2-[(5-chloro-1-naphthoyl)amino]-1-3-chlorophenyl)propyl hydrogen succinate

To a solution ofN-[(1RS,2SR)-1-(4-tert-butylbenzyl)-2-(3-chlorophenyl)-2-hydroxyethyl]-5-chloro-1-naphthamide(0.499 g, 0.985 mmol) and succinic chloride (0.38 g, 2.46 mmol) inacetonitrile (30 ml) was added 4-N,N-dimethylaminopyridine (0.24 g, 1.97mmol), and the mixture was stirred at 70° C. for 3 hrs. After coolingthe reaction solution to room temperature, water (30 ml) was added, andthe mixture was stirred as it was for 0.5 hr. The reaction solution wasacidified with dilute hydrochloric acid, and extracted twice with ethylacetate. The recovered organic layer was dried over anhydrous magnesiumsulfate and the solvent was evaporated under reduced pressure. Theobtained crude product was purified by silica gel column chromatography(hexane/ethyl acetate=2/1−1/1). Crystallization from diisopropylether-hexane gave the objective substance.

white crystal yield 0.325 g, 54% mp 161-162° C.; ¹H-NMR (CDCl₃, 300 MHz)δ 1.31 (9H, s), 2.63-2.84 (5H, m), 3.02 (1H, dd, J=4.1 Hz, 14.0 Hz),4.98-5.06 (1H, m), 5.97 (1H, d, J=9.3 Hz), 6.21 (1H, d, J=4.8 Hz), 7.11(2H, d, J=8.4 Hz), 7.18-7.54 (11H, m), 8.28 (1H, d, J=8.7 Hz); IR (KBr)3300-3020, 2961, 1734, 1644, 1532, 1213, 1165, 783 cm⁻¹;Anal. Calcd forC₃₄H₃₃Cl₂NO₅.0.5H₂O: C, 66.34; H, 5.57; N, 2.28. Found: C, 66.28; H,5.34; N, 2.28.

Example 393 sodium(1RS,2SR)-3-(4-tert-butylphenyl)-2-[(5-chloro-1-naphthoyl)amino]-1-(3-chlorophenyl)propyl succinate

To a solution of(1RS,2SR)-3-(4-tert-butylphenyl)-2-[(5-chloro-1-naphthoyl)amino]-1-(3-chlorophenyl)propyl hydrogen sucemate (217 mg, 0.358 mmol) in tetrahydrofuran(3 ml) was added 1N aqueous sodium hydroxide solution (0.36 ml, 0.36mmol), and the mixture was stirred at room temperature for 5 mm. Thesolvent of the reaction solution was evaporated under reduced pressure,and the obtained residue was crystallized from methanol-diethylether-hexane to give the objective substance.

white powder yield 200 mg, 89% mp 174-178° C.; ¹H-NMR (CDCl₃-CD₃OD, 300MHz) δ 1.30 (9H, s), 2.53-2.58 (2H, m), 2.65-2.83 (3H, m), 3.00 (1H, dd,J=2.7 Hz, 14.4 Hz), 4.89-4.98 (1H, m), 6.17 (1H, d, J=4.8 Hz), 7.12 (2H,d, J=8.4 Hz), 7.20-7.54 (11H, m), 8.28 (1H, d, J=8.4 Hz); IR (KBr) 3245,2965, 1730, 1640, 1574, 1418, 1157, 785 cm⁻¹; Anal. Calcd forC₃₄H₃₂Cl₂NO₅Na.1.0H₂O: C, 63.16; H, 5.30; N, 2.17. Found: C, 62.93; H,5.57; N, 2.04.

Example 394(1RS,2SR)-2-[(5-chloro-1-naphthoyl)amino]-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propylhydrogen succinate

To a solution of5-chloro-N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]naphthalene-1-carboxamide(0.549 g, 1.094 mmol) and succinic chloride (0.42 g, 2.73 mmol) inacetonitrile (30 ml) was added 4-N,N-dimethylaminopyridine (0.27 g, 2.19mmol), and the mixture was stirred at 70° C. for 3 hrs. After coolingthe reaction solution to room temperature, water (30 ml) was added, andthe mixture was stirred as it was for 0.5 hr. The reaction solution wasacidified with dilute hydrochloric acid, and extracted twice with ethylacetate. The recovered organic layer was dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theobtained crude product was purified by silica gel column chromatography(hexane/ethyl acetate=2/1−1/1). Crystallization from diisopropylether-hexane gave the objective substance.

white crystal yield 0.408 g, 62% mp 228-229° C.; ¹H-NMR (CDCl₃-DMSO-d₆,300 MHz) δ 2.65-2.79 (4H, m), 2.87 (1H, dd, J=11.7 Hz, 13.5 Hz), 3.13(1H, dd, J=3.3 Hz, 14.1 Hz), 4.94-5.04 (1H, m), 6.21 (1H, d, J=6.0 Hz),7.08-7.23 (5H, m), 7.38 (2H, d, J=7.8 Hz), 7.47-7.54 (6H, m), 7.75 (1H,d, J=9.6 Hz), 8.25 (1H, d, J=8.4 Hz); IR (KBr) 3300-2640, 1730, 1636,1528, 1510, 1323, 1221, 1177, 1155, 1109 cm⁻¹; Anal. Calcd forC₃₁H₂₄ClF₄NO₅.0.3H₂O: C, 61.30; H, 4.08; N, 2.31. Found: C, 61.21; H,3.72; N, 2.36.

Example 395 sodium(1RS,2SR)-2-[(5-chloro-1-naphthoyl)amino]-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propylsuccinate

To a solution of(1RS,2SR)-2-[(5-chloro-1-naphthoyl)amino]-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propylhydrogen succinate (214 mg) in tetrahydrofuran (3 ml) was added1N-aqueous sodium hydroxide solution (0.36 ml, 0.36 mmol), and themixture was stirred at room temperature for 5 min. The solvent of thereaction solution was evaporated under reduced pressure, and theobtained residue was crystallized from methanol-diethyl ether-hexane togive the objective substance.

pale-yellow amorphous powder yield 132 mg) ¹H-NMR (CDCl₃-DMSO-d₆-CD₃OD,300 MHz) δ 2.54-2.79 (4H, m), 2.91 (1H, dd, J=11.7 Hz, 14.1 Hz), 3.08(1H, dd, J=2.6 Hz, 14.0 Hz), 4.86-4.93 (1H, m), 6.18 (1H, d, J=5.7 Hz),7.04-7.22 (4H, m), 7.26 (1H, d, J=6.6 Hz), 7.39 (2H, d, J=8.4 Hz),7.47-7.55 (6H, m), 8.26 (1H, d, J=8.1 Hz); IR (KBr) 3650-2940, 1730,1640, 1574, 1539, 1512, 1327, 1159, 1123 cm⁻¹; Anal. Calcd forC₃₁H₂₃ClF₄NO₅Na.1.1H₂O: C, 57.84; H, 3.95; N, 2.18. Found: C, 57.68; H,3.97; N, 2.13.

Example 396(1RS,2SR)-1-(4-fluorophenyl)-2-[(4-fluoro-1-naphthoyl)amino]-3-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)propylhydrogen succinate

To a solution of4-fluoro-N-{(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]ethyl}-1-naphthamide(0.278 g, 0.508 mmol) and succinic chloride (0.20 g, 1.27 mmol) inacetonitrile (30 ml) was added 4-N,N-dimethylaminopyridine (0.12 g, 1.02mmol), and the mixture was stirred at 70° C. for 3 hrs. After coolingthe reaction solution to room temperature, water (30 ml) was added, andthe mixture was stirred as it was for 0.5 hr. The reaction solution wasacidified with dilute hydrochloric acid, and extracted twice with ethylacetate. The recovered organic layer was dried over anhydrous magnesiumsulfate and the solvent was evaporated under reduced pressure. Theobtained crude product was purified by silica gel column chromatography(hexane/ethyl acetate=2/1−1/1). Crystallization from diisopropylether-hexane gave the objective substance.

white crystal yield 0.184 g, 56% mp 196-197° C.; ¹H-NMR (CDCl₃-DMSO-d₆,300 MHz) δ 2.71-2.75 (4H, m), 2.78 (1H, dd, J=11.4 Hz, 14.4 Hz), 2.98(1H, dd, J=3.6 Hz, 14.7 Hz), 4.89-4.98 (1H, m), 6.33 (1H, d, J=4.5 Hz),7.01-7.16 (6H, m), 7.27 (1H, dd, J=5.4 Hz, 8.1 Hz), 7.38-7.54 (6H, m),8.05 (1H, d, J=7.8 Hz); IR (KBr) 3285-2620, 1728, 1512, 1279, 1223,1159, 1084 cm⁻¹; Anal. Calcd for C₃₂H₂₃F₆NO₇.0.5H₂O: C, 58.54; H, 3.68;N, 2.13. Found: C, 58.76; H, 3.85; N, 2.31.

Example 397 sodium(1RS,2SR)-1-(4-fluorophenyl)-2-[(5-fluoro-1-naphthoyl)amino]-3-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)propylsuccinate

To a solution of(1RS,2SR)-1-(4-fluorophenyl)-2-[(4-fluoro-1-naphthoyl)amino]-3-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)propylhydrogen succinate (145 mg) in tetrahydrofuran (3 ml) was added 1Naqueous sodium hydroxide solution (0.22 ml, 0.22 mmol), and the mixturewas stirred at room temperature for 5 min. The solvent of the reactionsolution was evaporated under reduced pressure, and the obtained residuewas crystallized from methanol-diethyl ether-hexane to give theobjective substance.

white powder yield 79 mg) ¹H-NMR (CDCl₃-DMSO-d₆-CD₃OD, 300 MHz) δ2.54-2.76 (4H, m), 2.85 (1H, dd, J=11.6 Hz, 14.3 Hz), 2.98 (1H, dd,J=3.5 Hz, 14.3 Hz), 4.80-4.86 (1H, m), 6.21 (1H, d, J=4.8 Hz), 7.03-7.14(6H, m), 7.25 (1H, dd, J=5.4 Hz, 7.8 Hz), 7.40 (1H, dd, J=6.5 Hz, 8.6Hz), 7.50-7.53 (4H, m), 8.04 (1H, d, J=8.7 Hz); IR (KBr) 3630-2930,1728, 1642, 1601, 1574, 1512, 1279, 1227, 1157, 1084 cm⁻¹; Anal. Calcdfor C₃₂H₂₂F₆NO₇Na.1.5H₂O: C, 55.18; H, 3.62; N, 2.01. Found: C, 55.41;H, 3.67; N, 2.00.

INDUSTRIAL APPLICABILITY

Since Compound (I) and Compound (I′) of the present invention havesuperior cholesteryl ester transfer protein inhibitory action and thelike, pharmaceutical agents containing these compounds can be usedsafely and advantageously as, for example, lipid-lowering agents and thelike.

This application is based on a patent application No. 19280/2001 filedin Japan, the contents of which are hereby incorporated by reference.

1. A compound represented by the formula

wherein Ar¹ is an aromatic ring group optionally having substituents,Ar² is an aromatic ring group having substituents, OR″ is an optionallyprotected hydroxyl group, R is an acyl group, and R' is a hydrogen atomor a hydrocarbon group optionally having substituents, or a saltthereof; except tert-butylbenzyl-[2(S)-hydroxy-2-thiazol-2-yl-1(S)-(4-trifluoromethyl-benzyl)-ethyl]-carbamate.2. The compound of claim 1, wherein Ar¹ is a 5- or 6-membered aromaticring group optionally having substituents.
 3. The compound of claim 1,wherein Ar¹ is a phenyl group optionally having substituents.
 4. Thecompound of claim 1, wherein Ar² is a 5- or 6-membered aromatic ringgroup having substituents.
 5. The compound of claim 1, wherein Ar² is aphenyl group having substituents.
 6. The compound of claim 1, wherein Ris a group represented by the formula R^(1N)CO— (R^(1N) is a hydrocarbongroup optionally having substituents or a heterocyclic group optionallyhaving substituents).
 7. The compound of claim 6, wherein R^(1N) is acyclic hydrocarbon group optionally having substituents or aheterocyclic group optionally having substituents.
 8. The compound ofclaim 1, wherein R″ is a hydrogen atom or an acyl group.
 9. The compoundof claim 1, wherein R″ is a group represented by the formula R¹⁰CO— (R¹⁰is a hydrocarbon group optionally having substituents or a heterocyclicgroup optionally having substituents).
 10. The compound of claim 8,wherein R¹⁰ is an alkyl group optionally having substituents.
 11. Thecompound of claim 1, wherein R″ is a hydrogen atom.
 12. The compound ofclaim 1, wherein R′ is a hydrogen atom.
 13. The compound of claim 1,wherein R is a group represented by the formula R^(1N)CO— (R^(1N) is acyclic hydrocarbon group optionally having substituents or aheterocyclic group optionally having substituents), R″ is a hydrogenatom and R′ is a hydrogen atom.
 14. The compound of claim 1, wherein Ar¹is a 5- or 6-membered aromatic ring group optionally having substituentsselected from halogen atom, optionally halogenated lower alkyl group,optionally halogenated lower alkoxy group and aryloxy group optionallyhaving substituents, Ar² is a 5- or 6-membered aromatic ring grouphaving substituents selected from halogen atom, optionally halogenatedlower alkyl group and optionally halogenated lower alkoxy group, R is aC₁₋₆alkoxy-carbonyl, a C₁₋₆alkyl-carbonyl, a C₆₋₁₀aryl-carbonyl,dihydronaphthalenecarbonyl, tetrahydronaphthalenecarbonyl,benzocycloheptenecarbonyl or benzocyclooctenecarbonyl, each of which mayhave substituent(s) selected from halogen atom, optionally halogenatedC₁₋₆alkoxy and optionally halogenated C₁₋₆alkyl, R″ is a hydrogen atom,and R′ is a hydrogen atom.
 15. The compound of claim 14, wherein the 5-or 6-membered aromatic ring group is a phenyl group, a pyridyl group, athienyl group, a furyl group or a thiazolyl group.
 16. The compound ofclaim 14, wherein the 5- or 6-membered aromatic ring group is a phenylgroup, a pyridyl group or a thienyl group, and R is naphthalenecarbonyl,dihydronaphthalenecarbonyl, tetrahydronaphthalenecarbonyl,benzocycloheptenecarbonyl or benzocyclooctenecarbonyl, each of which mayhave substituent(s) selected from halogen atom, optionally halogenatedC₁₋₆alkoxy and optionally halogenated C₁₋₆alkyl.
 17. The compound ofclaim 1, which isN[(1RS2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-fluoromethyl)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,4-fluoro-N-((1R,2S)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide,N-[(1R,2S)-2-(4-fluorophenyl)-2-hydroxy-1-[3-1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-5,6-dihydronaphthalene-1-carboxamide,N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-1-carboxamide,4-fluoro-N-[(1R,2S)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]naphthalene-1-carboxamide,N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-5,6,7,8-tetrahydrobenzo[a]cyclooctene-1-carboxamide,N-[(1RS2SR)2-(4-fluorophenyl)-2-hydroxy-1-(4-isopropylbenzyl)ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,N-((1RS,2SR)-2-(3-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,N-((1RS,2SR)-2-hydroxy-2-(4-phenoxyphenyl)-1-((4(trifluoromethyl)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,N-((1RS,2SR)-2-(4-chlorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,N-((1RS,2SR)-2-hydroxy-2-(4-(phenyloxy)phenyl)-1-((3-((1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,N-((1RS,2SR)-2-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-2-hydroxy-1-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,N-((1RS,2SR)-2-(2-fluoropyridin-4-yl)-2-hydroxy-1-((3-(1,1,2,2-tetrafluoroetoxy)phenyl)mehyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene1-carboxamide,N-((1RS,2RS)-2-(6-fluoropyridin2-yl)-2-hydroxy-1-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide,N-[(1RS,2SR)-1-(4-tert-butylbenzyl)-2-(3-chorophenyl)-2-hydroxyethyl]-5-chlorol-1-naphthamide,4-fluoro-N-{(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]ethyl}-1-naphthamideor a salt thereof.
 18. A prodrug of a compound represented by theformula

wherein Ar¹ is an aromatic ring group optionally having substituents Ar²is an aromatic ring group having substituents, OR″ is an optionallyprotected hydroxyl group, R is an acyl group, and R′ is a hydrogen atomor a hydrocarbon group optionally having substituents, or a saltthereof, except tert-butylbenzyl-[2(S)-hydroxy-2-thiazol-2-yl-1(S)-(4-trifluoromethyl-benzyl)-ethyl]-carbamate.19. A pharmaceutical composition comprising a compound represented bythe formula

wherein Ar¹ is an aromatic ring group optionally having substituents,Ar² is an aromatic ring group having substituents, OR″ is an optionallyprotected hydroxyl group, R is an acyl group, and R′ is a hydrogen atomor a hydrocarbon group optionally having substituents, or a salt thereofof a prodrug thereof.
 20. The composition of claim 19, which is acholesteryl ester transfer protein inhibitor.
 21. The composition ofclaim 19, which is a high density lipoprotein-cholesterol elevatingagent.
 22. The composition of claim 19, which is a low densitylipoprotein-cholesterol lowering agent.
 23. The composition of claim 19,which is an very low density lipoprotein-cholesterol lowering agent. 24.The composition of claim 19, which is a triglyceride lowering agent. 25.The composition of claim 19, which is a prophylactic or therapeuticagent of acute coronart syndrome.
 26. The composition of claim 19, whichis a prophylactic or therapeutic agent of acute cardiac infarction. 27.The composition of claim 19, which is a prophylactic or therapeuticagent of unstable angina pectoris.
 28. The composition of claim 19,which is a prophylactic or therapeutic agent of PTCA or arterialrestenosis after stent placement.
 29. The composition of claim 19, whichis a prophylactic or therapeutic agent of peripheral arterial occlusion.30. The composition of claim 19, which is a prophylactic or therapeuticagent of hyperlipidemia.
 31. The composition of claim 19, which is aprophylactic or therapeutic agent of cerebral infarction.
 32. Thecomposition of claim 19, which is a prophylactic or therapeutic agent ofstroke.
 33. The composition of claim 19, which is a suppressor ofprogression of focal arteriosclerosis.
 34. A cholesteryl ester transferprotein inhibitor comprising a compound represented by the formula

wherein Ar¹ is an aromatic ring group optionally having substituents,Ar² is an aromatic ring group optionally having substituents, OR″ is anoptionally protected hydroxyl group, R is an acyl group, and R′ is ahydrogen atom or a hydrocarbon group optionally having substituents, ora salt thereof or a prodrug thereof.
 35. The agent of claim 34, which isa prophylactic or therapeutic agent of hyperlipidemia.
 36. The agent ofclaim 34, which is a prophylactic or therapeutic agent of acute coronarysyndrome.
 37. The agent of claim 34, which is a prophylactic ortherapeutic agent of acute cardiac infarction.
 38. The agent of claim34, which is a prophylactic or therapeutic agent of unstable anginapectoris.
 39. The agent of claim 34, which is a prophylactic ortherapeutic agent of PTCA or arterial restenosis after stent placement.40. The agent of claim 34, which is a prophylactic or therapeutic agentof peripheral arterial occlusion.
 41. The agent of claim 34, which is aprophylactic or therapeutic agent of cerebral infarction.
 42. The agentof claim 34, which is a prophylactic or therapeutic agent of stroke. 43.The agent of claim 34, which is a suppressor of progression of focalarteriosclerosis.
 44. A method of inhibiting cholesteryl ester transferprotein in a mammal, which comprises administering an effective amountof a compound of claim 1 or a salt thereof to the mammal.
 45. A methodfor the prophylaxis or treatment of hyperlipidemia in a mammal, whichcomprises administering an effective amount of a compound of claim 1 ora salt thereof to the mammal.
 46. A method for the prophylaxis ortreatment of acute coronary syndrome in a mammal, which comprisesadministering an effective amount of a compound of claim 1 or a saltthereof to the mammal.
 47. A method for the prophylaxis or treatment ofacute cardiac infarction in a mammal, which comprises administering aneffective amount of a compound of claim 1 or a salt thereof to themammal.
 48. A method for the prophylaxis or treatment of unstable anginapectoris in a mammal, which comprises administering an effective amountof a compound of claim 1 or a salt thereof to the mammal.
 49. A methodfor the prophylaxis or treatment of PTCA or coronary resteiiosis afterstent placement in a mammal, which comprises administering an effectiveamount of a compound of claim 1 or a salt thereof to the mammal.
 50. Amethod for the prophylaxis or treatment of peripheral arterial occlusionin a mammal, which comprises administering an effective amount of acompound of claim 1 or a salt thereof to the mammal.
 51. A method forthe prophylaxis or treatment of cerebral infarction in a mammal, whichcomprises administering an effective amount of a compound of claim 1 ora salt thereof to the mammal.
 52. A method for the prophylaxis ortreatment of stroke in a mammal, which comprises admimistering aneffective amount of a compound of claim 1 or a salt thereof to themammal.
 53. A method of suppressing progression of focalarteriosclerosis in a mammal, which comprises administering an effectiveamount of a compound of claim 1 or a salt thereof to the mammal.
 54. Amethod of inhibiting cholesteryl ester transfer protein in a mammal,which comprises administering an effective amount of a compoundrepresented by the formula (I′) of claim 34 or a salt thereof or aprodrug thereof to the mammal.
 55. A production method of claim 1 or asalt thereof, which comprises subjecting a compound represented by theformula

wherein each symbol is as defined in claim 1, or a salt thereof to anacylation reaction to give a compound represented by the formula

wherein each symbol is as defined in claim 1, or a salt thereof, and,where desired, subjecting the compound to a hydroxyl group-protectingreaction.